Summary

These notes cover the topics of pharmacokinetics, pharmacodynamics, and pharmacogenetics in relation to drug response. The document details the movement of drugs through the body and their effects on the body. The study material also includes information about the genetic factors affecting drug response and different drug formulations.

Full Transcript

MĀTAI TAKA RONGOĀ NURSE204 PHARMACOKINETICS, DYNAMICS, Emily Grout [email protected] GENETICS LEARNING OBJECTIVES PK + PD is important for nurses to know to...

MĀTAI TAKA RONGOĀ NURSE204 PHARMACOKINETICS, DYNAMICS, Emily Grout [email protected] GENETICS LEARNING OBJECTIVES PK + PD is important for nurses to know to understand what they are doing within their role and to be able to have knowledge around meds + Develop an understanding of pharmacokinetics identifying potential harm/mistakes and to challenge this.. As well as to educate patients, Develop an understanding of pharmacodynamics gaining informed consent. Develop an understanding of pharmacogenetics (in reference to drug response) PHARMACOKINETICS Pharmaco Drugs Kinetics Moving The study of where the drugs go through the body (their fate!) Looks into metabolism Through to excretion ENTRY AND DISTRIBUTION Drugs need entry (to work) and distribution (to get to site of action) Action is normally temporary (detoxification and elimination) Active components gets detoxified/metabolised, becoming chemically inactive in the body or then something that can be removed through excretion/ elimination. Duration of this considers: the type of medication, the dosage, what is happening inside the body, a person's genetics, and a person's ability to metabolise + excrete different drugs. PHARMACODYNAMICS The effect of drugs on the person Once the drug reaches the site of action, pharmacodynamics determine the intensity of the response The impact of drugs on the body PHARMACOGENOMICS The role of the genome in drug response Can change now drugs work, greater or poorer.. How does the genetic make up affect drug response? Genetic variation can alter pharmacokinetic or pharmacodynamics response. Deviates from “One-dose-fits-all” approaches Generally, can come across people who do not like certain drugs; it may not work for them, or too well for them which Key genes include; can leave a person with adverse drug reactions or unpleasant Cytochrome P450s side effects... VKORC1 TPMT PHARMACOKINETICS Drug movement through the body and what happens to that drug as it moves 4 phases Absorption Distribution Metabolism Excretion Act together to determine the concentration of drugs at the site of action PHARMACOKINETICS *formulation of the drug : The breaking down and separation of any carrier molecules from the active component, and dissolution: depending on the formulation of the drug, determines how easy it is for the body to complete these processes, and therefore now quickly can start to enter the system. Separation of active ingredient from carriers (disintegration, disaggregation, dissolution) Movement of a drug from the site of administration into the blood Distribution from the blood into the interstitial space of tissues, and into theHow cells it gets to the site of action. Biotransformation, enzymatic alteration of drug structure = turning the drug into something that is more functional, or metabolising the active component into something inert so that it can be excreted. Movement of the drug and metabolites out of the body E.g : Sweat, exhalation, feces, breast milk… Mostly oral… IV… Following principles of diffusion & concentration gradients.. IM, topical… LIBERATION Common routes of drug administration; Injection (IM or IV) Inhalation Dermal Rectal Buccal = between gums and cheek of the mouth Sublingal = underneath the tounge Intra-articular = direct delivery into a joint space (knee - arthritis) LIBERATION Many drugs are formulated into tablets, or other medication forms A forumation is a mixture containing the active ingredient, and 1+ inactive substances added to increase absorption to dilute (particularly when drugs are strong and hard to accurately measure) control the release of drugs It's important that drugs are mixed: combinations help to increase absorption, help dilute otherwise small volumes of active ingredients would be hard to dose, to measure and deliver… liberation formulas can also be used to control the release of drugs e.g. how quick or slow drugs can be released into the body. LIBERATION Types of release; Immediate – active ingredient is released without delay Delayed – active ingredient is released sometime after the drug has been taken (usually oral delivery) Extended – active ingredient is released over an extended period of time, allowing reduced dosage frequency (compared to immediate or delayed) Where the active ingredient is buried in a semi- Soluble drug insoluble matrixes so that it takes a longer time to be broken down = the active ingredient is being The body (that can be better or worse at dissolving matrixes) released at a slower rate over a longer period of time… targets the matrixes and with the movement releases drug particles at a steady or prolonged pace. Common when reducing the dosage frequency to meet a persons need. Slowly dissolving matrix LIBERATION Effervescence Creates bubbles = a physical change which speeds up the breakdown of the drug. Reactions that form CO2 bubbles Bubbles break up the particles, and increase drug release Enteric coatings Like gelatine shell, encapsulate drugs Seen in drugs that may be sensitive to stomach conditions The coating prevents early breakdown of the drug so that it can travel past the stomach to avoid the harsh, acidic environment therefore the compound can remain intact - avoiding pH lonization which can impact the ability for the drug to be absorbed into the body. also common with drugs that can be irritating to the gastric system = beneficial for the drug to be broken down later to avoid an upset stomach. ABSORPTION → A → B.. Movement through many layers of the body to complete absorption.. The process of the active drug reaching the bloodstream Depends on the compound... It will need to go through a certain transporter in order to move.. E.g. From the intestines → the Some compounds follow the bloodstream.. standard process of diffusion = From a high → low gradient e.g. From the intestines → the bloodstream.. E.g. ATP or concentration gradients to work across membranes and absorb into the bloodstream. ABSORPTION – BIOAVAILABILITY The rate and concentration where a drug reaches systemic circulation Described as a % of the drug initially administered Eg: drugs administered IV would have a bioavailability of 100% because 100% of the drug would make it into systemic circulation IV paracetamol delivery has a bioavaiability of 100%, oral bioavaiability may be 79% E.g. Administered 1000mg but only 790mg of that are going to make it into systemic Bioavaiability can be effected by two mechanisms; circulation by the time It has been dissolved, moved across different membranes, and by the time it has passed through the liver and any other metabolic steps… Ability to pass through the lipid membranes IV = 100% bioavailability because it bypasses all these process & is delivered immediately into the bloodstream. Drugs must pass through membranes to enter the blood, and once in the blood must pass trhough a membrane to reach the site of action, metabolism, and excretion Can the drug cross membranes freely or does it rely on transporters? First pass metabolism (first pass effect) ABSORPTION - MEMBRANES Phospholipid bilayers surround all the cells Semi permeable Lipid lined = hydrophobic → for a drug to pass through the membrane it also has to be lipid-soluble.. OR… How can drugs pass through? Channels or pores Transport systems Direct penetration of the membrane = the drug is also lipid-soluble. ABSORPTION – CHANNELS AND PORES Uncommon for drugs to cross using channels or pores Channels in membranes are very small and highly specific Controlled entrance into cells → protection mechanism.. Allow for the passage of small compounds (like potassium or sodium) if the channel is the right fit ABSORPTION – TRANSPORT SYSTEMS Act as carriers, moving drugs from one side of the membrane to the other Some are active (require expenditure of energy – ATP) All are selective (very specific for the molecule) Highly important for drug transit ABSORPTION - PGP P-Glycoprotein (PGP) is a multidrug transporter protein Transports a number of drugs out of the cell, present in the liver, kidney, placenta, intestine, capillaries of the brain Think: protecting foetus from drugs & harmful toxins.. Think: blood / brain barrier ~ keeping certain drugs & harmful toxins out of the brain.. Drugs can use the PGP system to move from x1 side to the other as long as the drug is trying to enter a tissue where PGP is present. *1-2 page article for revision - on reading list ABSORPTION – DIRECT PENETRATION OF THE MEMBRANE Most drugs are too large to pass through channels or pores Most drugs lack transport systems that allow them to cross the membranes Many drugs directly penetrate the membrane and can so based on solubility Like dissolves like Lipid-soluble drugs can directly penetrate through the cell membrane.. QUICK REVISION ON POLARITY AND RELATIVE SOLUBILITY Molecules interact with others to form compounds May be ionically bonded (donation of electrons) Or covalently bonded (sharing electrons) Determines whether or not they are polar or non-polar. (H2O) Covalent bonds can be polar or non-polar based on distribution of electrical charge H2 would be non-polar because both atoms have the same overall distribution of atoms H2O is polar because the oxygen atom has a greater electrical charge than the two H2 Ionic bonds are always polar because the donation of an ion shifts the distribution QUICK REVISION ON POLARITY AND RELATIVE SOLUBILITY Polar compounds will dissolve in polar solvents NaCl (polar compound) will readily dissolve in H2O (polar solvent) Non-polar compounds will dissolve in polar solvents (H2O) PHOSPHOLIPIDS Type of lipid with a hydrophilic “head” and two hydrophobic “tails” Hydro (water), philic (to attract), phobic (to hate) Phospholipids are complex lipids that contain phosphorus. They are the main component of the plasma membrane, and may transport other lipids in the blood The fatty acid tails of are lipid based Keeps ions, proteins, and molecules from diffusing Hydrophilic, and insoluble to most water-soluble molecules PH DEPENDANT IONISATION Some drugs can change form depending on pH (pronation) which will alter their solubility Protonation: A chemical process involving movement of charges which changes their solubility.. Remember acids are proton donors (H+) and bases are proton acceptors When an acid donates a proton (with a positive charge) the acid becomes negatively charge, and visa versa with bases (Ionisation) Ionisation changes the chemical property, and ionised forms of acids/bases are not lipid soluble ABSORPTION – FACTORS THAT AFFECT IT Absorption is the movement of the drug into the blood stream The rate of absorption determines the rate in which the effects will begin The amount of absorption determines the intensity of the effects Factors affecting absorption; Have villi which create a large Rate of dissolution How quickly did the drug dissolve? surface area. A larger surface area = more surface for the molecules to Surface area (of the site of absorption ie; stomach vs small intestine SA) travel across and be absorbed into the body.. Blood flow (areas with fast blood flow will maintain the concentration gradient) Lipid solubility (lipid soluble drugs can cross the membranes) pH partitioning CHARACTERISTICS OF ADMINISTRATION ROUTES Route Absorption barriers Absorption pattern Advantages Disadvantages Unless using an antidote.. Intravenous (IV) None (absorption is bypassed) Instantaneous Rapid onset, and hence ideal for Irreversible, Expensive, Inconvenient emergencies Difficult to do, and hence poorly suited Precise control over drug levels for self-administration Permits use of large fluid volumes Risk of fluid overload, infection, and Permits use of irritant drugs embolism Drug must be water soluble Intramuscular Capillary wall (easy to pass) Rapid with water-soluble drugs Permits use of poorly soluble drugs Possible discomfort (IM)/Subcutatneous Slow with poorly soluble drugs Permits use of depot preparations Inconvenient (subQ) Potential for injury Oral (PO) Epithelial lining of GI tract; capillary Slow and variable Easy Variability wall Convenient Inactivation of some drugs by gastric Inexpensive acid and digestive enzymes Ideal for self-medication Possible nausea and vomiting from local Potentially reversible, and hence safer irritation than parenteral routes Patient must be conscious and cooperative IF IV ALLOWS INSTANTANEOUS DELIVERY WITH 100% BIOAVAILABILITY WHY DON’T WE USE IT FOR EVERYTHING? Not all drug formulations are appropriate for IV administration! not all drug formulations are appropriate for IV administration.. Some Some drugs drugs (like (like adrenaline) adrenaline) can be could beused usedIM, IM,IV,IV,subQ subQoror more… more → but But concentrations will concentrations will differ differdepending dependanton delivery. on delivery! DRUG MOVEMENT POST ABSORPTION Thinking back to digestion… everything that is absorbed through the gut lumen must past through the liver (portal vein) before going into circulation Important to prevent poisoning ourselves! For some drugs, this changes nothing For other drugs they are metabolised through the liver In some drugs the first pass effect changes nothing... In some cases, It changes a lot and the drug has hugely changed through the first pass effect, therefore what makes It into systemic circulation is different → the liver contains enzymes that are good at metabolising substances, or the concentration of the active component can sometimes metabolising drugs all the way or into different forms. become quite variable based on what happened during first pass. DISTRIBUTION The movement from the blood to the interstitial space of tissues, and into the cells Determined by; Blood flow to tissues (The perfussion of the tissues). Movement of the drug out of the vascular system Movement of the drug into the cells DISTRIBUTION – TO TISSUES Carrying the drug from the blood into the tissues (and organs) Rate dependant on blood flow This is not a highly rate-limiting step – most tissues are well perfused! Abscesses and tumours with low blood flow can affect drug therapy * will not get the same Thus large abscesses need to be drained for antibiotics to reach the site of infection distribution of the drug compared to highly perfused tissues. Is this the same for pressure injuries that become infected & other wounds that require drug therapy? DISTRIBUTION – LEAVING THE BLOOD STREAM Once the drug has reached the target tissues (via the blood stream) it needs to leave to act on the relevant tissue or undergo metabolism and excretion Drugs leave at the capillary beds = gaps to pass. Gaps are large enough for compounds and molecules to pass freely Following principles of diffusion = high → low gradient to pass. Lipid soluble molecules can pass through gaps or through the capillary wall *Leaving the bloodstream to act on tissues/ cells e.g. site of action.. DISTRIBUTION – ACROSS THE BBB Wanting to protect the brain = the gaps within the capillary beds are harder to pass through. The brain is different Unique capillaries in the CNS form the blood-brain barrier Junctions are much tighter to control the passage of molecules! Drugs must be lipid soluble or have a transport system to be able to pass through the blood-brain barrier DISTRIBUTION – ACROSS THE PLACENTA The membranes surrounding the placenta generally separate maternal and foetal circulation Some lipid-soluble or non-ionised compounds can cross the membrane Drugs that can cross may cause harm Is why some drugs are contraindicated during pregnancy.. DISTRIBUTION – PROTEIN BINDING Drugs can bond with proteins through the body A very important example is plasma albumin (the most abundant plasma protein) Plasma albumin is large (69 kDa), and will always be present in the blood stream Is not able to pass through anything. Drugs can reversibly bind to albumin Only some can be bound at each point Those that are bound cannot leave the blood stream, can’t reach their target site, can’t be metabolised, and can’t be excreted Because they are stuck to the protein. Staying bound increases the distribution of the drug and increases the half life The drug takes longer to reach the tissues/cells meaning they are prolonged in the The drug can unbind from albumin through principles of diffusion ~ maintaining equilibrium of what is in the body. tissues vs the blood… Other drugs can release the drug binding Important! Another drug that a person may take, may have a greater affinity for the plasma proteins therefore, they are A key concept in drug interactions! stickier and want the space on the albumin ~ once that drug is absorbed they will occupy the albumin and 'kick' anything else off that was already there... = the body suddenly gets a free drug that was bound, released into the bloodstream and going out into the tissues… A high influx = some drugs are plasma bound and cannot be administered with other drugs that are also plasma bound in case of greater affinity of the second drug potentially causing a sudden influx e.g. An overdose… DISTRIBUTION – PROTEIN BINDING Even though a drug can bind to protein only some molecules can be bound at any time The strength of the interaction between the drug and the protein determines what stays attached Albumin and warfarin have a strong attraction! 99% of warfarin molecules in the plasma are protein bound Because of this strong attraction, warfarin has quite a controlled release - 1% is free following the principles of diffusion. Gentamicin and albumin have a relatively weak interaction 10% protein bound Meaning gentamicin 90% free has a faster release. PROTEIN BINDING AFFECTS HALF LIFE As long as the drug reversibly binds, the binding is in equilibrium (bound and unbound) As the unbound portion is metabolised and excreted from the body the bound form will be released to maintain equilibrium This increases the life of the drug within the system Strong protein binding ~ expected to see: A longer life of the drug within the system because It is released slower.. If a drug has permanent binding to a protein (not a good drug) It will stick to the protein forever until the protein is digested & recycled. DISTRIBUTION – INTO THE CELLS Some drugs enter the cell for their site of action Some bind onto the outside of a cell All drugs enter the cell for metabolism and excretion What dictates entry into a cell is the same as crossing all other membranes Lipid solubility Transport systems METABOLISM Biotransformation – chemically altering the drug structure Mostly happens in the liver Following GI absorption METABOLIC – HEPATIC ENZYMES Most (75%) hepatic metabolism is performed by cytochrome P450 (CYP) superfamily CYP are membrane proteins located in the mitochondria or the endoplasmic reticulum Present in most tissues in the body CYPs may metabolise one or many substrates Deactivating or activating drugs Three families of CYP metabolise drugs; CYP1, CYP2, CYP3 And there’s lots of variants of each! Named CYP1A2, CYP2D6, CYP2C9 etc etc. Expecting to see population variation toward drug reactions or the way drugs work on the body. Enzymes removes a group = making it more polar therefore easier to dissolve in urine & be excreted from the body. Metabolism has 6 outcomes = more soluble An addition of an Increased renal excretion of drugs OH group which makes it more Inactivation of drugs soluble to be able to Increased effectivity be excreted through the urinary Activation of pro-drugs system. Increased toxicity Decreased toxicity Metabolism has 6 outcomes Increased renal excretion of drugs Inactivation of drugs Increased effectivity Activation of pro-drugs Increased toxicity From the active form of Decreased toxicity procaine → an inactive form of PABA by enzymes 'chewing' Off an extra section (breaking the bond) & replacing It with an H = taking It from an active compound → an inactive compound that can then be excreted from the body. Metabolism has 6 outcomes Increased renal excretion of drugs Inactivation of drugs Increased effectivity Activation of pro-drugs Increased toxicity Example: codeine - little effectiveness for pain management… Decreased toxicity Liver enzymes: CYP1’s metabolise codeine into morphine. Morphine = the active compound.. * increasing the effectiveness of the drug by turning it into something that can help with pain. Some people with high amounts of the CYP1 enzyme can turn codeine into morphine quite quickly whereas, some people who don't make lots of the enzyme report when taking codeine that they don't get the analgesic effect as they generally are unable to turn it into the pain- killing form. Metabolism has 6 outcomes Increased renal excretion of drugs Inactivation of drugs Increased effectivity Activation of pro-drugs Increased toxicity Decreased toxicity Metabolism has 6 outcomes Increased renal excretion of drugs Inactivation of drugs Increased effectivity Activation of pro-drugs Increased toxicity Decreased toxicity Acetaminophen = paracetamol is considered a safe drug but its metabolites are toxic.. Which is why there are lots of restrictions & regulations around how much paracetamol a person should be taking, because as it gets metabolised in the body, it creates a toxic compound.. WHAT ABOUT GRAPEFRUIT? Grapefruit contains a compound called ‘furocoumarins’ Which inhibits the enzyme : CYP34A.. Found in a number of plants; bergamot, figs – but best studied in grapefruit “Grapefruit” is an inhibitor of CYP3A4 The enzyme Is important for many drugs and their functions... If inhibited It could lead to having too much of the active compound in the body… OR the compound found in grape fruit can block the transporters which prevents the drug from being moved around and distributed into the tissues. METABOLISM - CONSIDERATIONS Age Full ability for metabolism is beyond 1 year old, hepatic system is not mature Older adults may have decreased metabolism and drug dosages may need to be adjusted to reduce the risk of toxicity Inhibition/activation of enzymes E.G. Through grape fruit. Change the rate of metabolism Some drugs may change the rate of CYP enzymes, or stimulate more production of CYP First-pass effect Drugs absorbed in the GI go through the HPV, in some instances metabolism can completely metabolise the drug (eg; Nitroglycerin) METABOLISM - CONSIDERATIONS Nutritional status Maybe cannot metabolise drugs?.. Enzymes (including hepatic enzymes require co-factors for function! Nutritional deficiencies can deprive the body of these) Can affect the metabolism of drugs - may not be able to metabolise drugs at all.. Drug competition If two drugs are metabolised in the same pathway, there may be competition leading to the accumulation of one drug to dangerous levels Enterohepatic recirculation Where the drug circulates from liver, to duodenum and back (via the bile duct, and the portal vein) – persisting for a long time EXCRETION The removal of drugs from the body Urine Bile Sweat Saliva Breast milk Exhaled air EXCRETION - KIDNEYS Renal excretion accounts for the majority of excretion routes When the kidneys are unhealthy (renal failure) the duration and intensity of drug responses can increase Drugs may persist or be more intense because it is not being excreted in the same way It has been taken in. Small molecules and fluids pass into the during GF Active transport systems (including PGP) move drugs from the blood into the urine FACTORS THAT ALTER KIDNEY EXCRETION pH pH ionisation alters the excretion of drugs Ions are not lipid soluble, and therefore cannot undergo passive tubular reabsorption and will remain in the urine for excretion Competition for active transport Transport systems can only carry a limited number of molecules at a time Drugs may be competitive for the same transport systems Can be exploited to slow drug excretion (eg: penicillin and probenecid) Age related renal function *Nephrons do not repair themselves & can get damaged... Non-renal drug excretion EXCRETION – NON-RENAL Drugs can be excreted in breast-milk in lactating people Potential to expose BF infants to drugs Passage of drugs between membranes is the same in the passage into breast-milk Lipid soluble drugs can readily enter Drugs can be excreted into the bile, which is secreted into the intestines and eventually faeces Drugs that are excreted into the bile can be reabsorbed in the small intestine (enterohepatic recirculation) Some drugs may be exhaled Eg: volatile anaesthetics Or leave through the sweat/saliva Eg: caffiene TIME COURSE DRUG RESPONSE Is patient variable: Because absorption, distribution, metabolism, and excretion alter drug responses it is possible to determine and control intensity and duration of drugs Can measure how much of a drug is in the body → using blood plasma levels.. is the best way to track the time course of a drug in the body. BLOOD PLASMA DRUG LEVELS Time course of drug action is often directly related to concentration of the drug in the plasma You can monitor plasma drug levels To adjust dosage and/or timing BLOOD PLASMA DRUG LEVELS Why do we use blood plasma when most sites of action are outside of the blood? It’s easy to measure You often can’t collect a sample from the site of action For most drugs there is a correlation between plasma concentration and drug response it's easy to measure. often cannot collect a sample from the site of action. for most drugs here is a correlation between plasma concentration and drug response. DRUG LEVELS Minimum effective concentration (MEC) The plasma level below therapeutic range/below where therapeutic effects will occur Minimal toxic concentration (MTC) Plasma levels are too high, dose needs to be small enough that the toxic The correct concentration of medicinal drugs, to concentration is not reached where it is needed, for as long as it is needed. The drug concentration should be abve the minimum effective concentration (for therapeutics), BUT below the minimal toxic concentration. This is the therapeutic range. THERAPEUTIC RANGE When blood plasma drug levels are between the MEC and MTC Drug can be used safely Depending on the width of the therapeutic range, depends on how safe it maybe to administer Drugs like paracetamol have wide therapeutic ranges and are fairly safe to administer (MTC ~30x higher than MEC) Drugs like lithium have narrow therapeutic ranges (MTC ~3x higher than MEC) – so must be dosed carefully The gap for a therapeutic range is very small - easy to be dosed too high leading to toxicity.. DRUG TIME COURSE Following oral administration of drugs blood plasma levels will not immediately rise Absorption must occur first! There is a latent period between administration and effect Rate determined by rate of absorption Duration of drug action is determined by metabolism and excretion As long as concentrations remain above the MEC there will be a therapeutic response HALF-LIFE As long as medication isn’t continually delivered, the concentration of a drug will decrease over time The half-life describes how quickly this occurs Measured by time required for the amount of drug to decrease by half (50%) Regardless of the dosage The half-life of morphine is 3 hours Concentrations of morphine in the body will decrease by 50% every three hours If you start at 50mg, at 3 hours 25mg will remain, 6 hours 12.5mg, 9 hours 6.25, 12 hours 3.125, 15 hours 1.5625mg Important when thinking about withdrawal from drugs… HALF-LIFE Short half-life = the body will deplete It quickly.. Long half-life = slower over time.. Half-life indicates dosage schedule If a drug has a short half-life, the dosing schedule needs to be more frequent to remain in the therapeutic range If a drug has a long half-life, the dosing schedule can be spaced while remaining in the therapeutic range *is staying in the body more so it is more likely to remain within the therapeutic range for longer.. REPEATED DOSES Multiple dose delivery results in accumulation Continual dosage can cause the drug to build up into a steady plateau In roughly 4 half lives THERAPEUTIC RANGE AND HALF LIFE PHARMACODYNAMICS PHARMACODYNAMICS What does the drug do to the body What are the mechanisms? DOSE-RESPONSE RELATIONSHIPS How does the size of the dose link to the intensity of the drug response? Phase 1; Curve is quite flat can’t see it on a linear scale! Dose is too low for a response Phase 2; Curve increases as the dose increases a larger response Phase 3; The curve levels off, an increased dose is no long able to elicit an increased response DOSE-RESPONSE CURVES CAN INDICATE POTENCY Maximal efficiency Largest effect a drug can produce Indicated by the height of the curve Potency The amount of drug needed to elicit a therapeutic effect Indicated by the position of the dose- response curve Potency and maximal efficiency are independent When a drug binds to a receptor It can stimulate it, making It work harder to produce something... OR a drug can simply sit in there and occupy it so that other endogenous ligands cannot bind, process and cause reactions within the body. DRUG RECEPTORS Drugs need to bind or interact to cause an effect There are a number of cellular drug receptors; enzymes, ribosomes, tubulin Drug + receptor = drug receptor complex + response Binding sites may accept endogenous molecules and drugs Made in the body. Drugs may function to mimic endogenous molecules Or inhibit their binding TYPES OF RECEPTOR G protein- coupled receptor Ligand-gated ion channel Embedded enzyme Transcription factor MEMBRANE PROTEINS Specific transport proteins that carry molecules from one side of the membrane to another Some drugs can sit in there and the block it preventing the movement of things from 1 place to another therefore whatever was going to happen within the certain cell can no longer happen because the gateway has been blocked by a molecule… LIGAND-GATED ION CHANNELS Located on the outside of membranes. Transmembrane proteins Allow the flow of ions (Na+, K+, Ca2+, Cl-) in response to the binding of a ligand Are common when using psychotropic drugs → moving molecules + stimulating different areas of the nearby cells.. G PROTEIN-COUPLED RECEPTORS Important drug targets Involved in mental, metabolic, endocrinological, immune, CVD, inflammatory, senses, and cancers Beta-2 adrenergic receptor (involved in asthma) is a GPCR Targeted by Salbutamol inhaler.. TRANSCRIPTION FACTORS Found inside the cell Slow acting (delayed responses) E.g. Prednisone -delayed formulation.. Regulate protein synthesis Activated by lipid soluble ligands Thyroid hormones Steroid hormones (progesterone, testosterone, cortisol) RECEPTORS AND SELECTIVITY Receptors are highly selective Not all ligands will inhibit/activate But some ligands will interact with receptors in lots of places Hence drugs like opioids help with pain… but also change respiration rates and bowel motility Because opioids can bind to receptors that are all over the Selective ≠ safe! body. SIMPLE OCCUPANCY THEORY The more receptors occupied the stronger the response 100% occupancy Maximal response occurs when all receptors are occupied 25% occupancy When delivering more of a drug - the receptors that are filled increase.. If they are all filled 100% occupancy = the maximal therapeutic response. MODIFIED OCCUPANCY THEORY Uses affinity and intrinsic activity Affinity – strength of interaction (between drug and receptor) Affinity is linked to potency Intrinsic activity – the ability of a drug to activate upon binding Drugs with high activity cause intense activation Drugs with low intrinsic activity only cause slight activation of the receptor DRUGS CAN BE AGONISTS OR ANTAGONISTS AGONISTS Activate receptors Neurotransmitters, hormones, endogenous receptors Drug binds to the receptor, and mimics normal function Has high affinity, and high intrinsic activity eg: Dobutamine mimics adrenaline at the heart, synthetic insulin mimics endogenous insulin, oral contraceptives mimic endogenous progesterone Made in the body, by the body ANTAGONISTS Prevent receptor activation by endogenous molecules Has affinity, but no intrinsic activity Binds in to a receptor, but doesn’t affect receptor, but does stop the endogenous molecule from binding and causing an effect Response to an antagonist depends on the concentration of the agonist. If no agonist is present, delivery of an antagonist will have no effect! eg: Antihistamines, bind into histamine receptors, preventing histamine from binding, naloxone, blocks morphine/opiate receptors Antidote for opioid overdose. By kicking plods off the receptors because it has a higher affinity for them. RECEPTOR SENSITIVITY Receptor numbers can change, and sensitivity to agonists can change If continually exposed to an agonist a cell may become less responsive (down- regulated) Driven by; lowered responsiveness to receptors, destruction of receptors) If continually exposed to antagonists, a cell may become more responsive (up regulated) and hypersensitive Driven by; increased synthesis of receptors NOT ALL DRUGS USE RECEPTORS Some drugs have chemical or physical reactions with other molecules in the body Antacids, antiseptics, osmotic agents (laxatives), chelating agents Are not acting with a receptor - but are Do not require drug receptors bringing in / drawing Neutralise in water which will then stomach acid & soften the stool. create a gelatinous layer to prevent reflux.. PATIENT VARIABILITY Drug response will vary between patients To measure the variability you need to know the endpoint result (therapeutic objective) Dosage concentration can be titred until patients elicit a response The midpoint of dosage is the average effective dose midpoint (ED50) Calculated by dosing a select population (in this figure, a population of 100! WHY USE THE ED50 Patients drug response may vary An initial dose of a drug will likely be an approximation and additional doses should be adjusted in response At the ED50, some patients would be under treated, and others over treated – thus we need to assess drug response THERAPEUTIC INDEX Measures safety A ratio of the LD50 (midpoint lethal dose) to ED50 A drug with a large/wide therapeutic index would be a relatively safe drug In comparison, a drug with a small/narrow therapeutic index would be relatively unsafe THERAPEUTIC INDEX It may take 1 patient 17mg of a drug to have an effect but for some people that some dose can be toxic! Which of these has a wide therapeutic index? Which has a narrow therapeutic index? Examine the proximity of the two curves If you were to pick the ED50 of each drug (X and Y) how close is this to any part of the LD50? TAKE AWAY POINTS LADME Receptor binding Therapeutic indexes

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