Pharmacology Study Guide PDF

VM 7522 Fundamentals of Pharmacology Study Guide for Pharmacokinetics...

VM 7522 Fundamentals of Pharmacology Study Guide for Pharmacokinetics Lectures #6-11 What are some factors that explain variability in clinical response? Pharmacokinetics (ADME) Pharmacodynamics (interaction drug-targets → drug effect) Variability in treatment response: key message - The average dose of a drug should not be expected to be effective and safe for the entire population - The use of an average drug dose/dosage regimen can have several consequences Tenet in Pharmacology - Drug molecules must be: - Present at its site of action - At a sufficient concentration - For a specific period of time → to exert a pharmacological effect Dosage regimen and the process of drug ADME dictate the concentration of a drug and the period of time at the site of action of the drug Margin of Safety (MOS): difference between the minimum and maximum effective limits Pharmacokinetics: the study of the time course of drug concentrations in the body The 4 key physiological processes that govern the movement of a drug in the body are: - Absorption - Distribution - Metabolism - Excretion (ADME) Potential consequences of polymorphisms on pharmacology: Drug Absorption (A) - The movement of drug molecules from the site of administration into the blood - When the drug is given by the intravascular route of drug administration there is NO drug absorption - From a clinical standpoint it is important to remember that the process of absorption delays the appearance of drug in the blood, and thus delays drug action Rate and extent of drug absorption affect plasma concentration, which in turn influences the drug effect Factors that affect the rate and extent of drug absorption - Anatomical barriers - Passive transcellular transport - Paracellular transport - Facilitated transport influx - Facilitated transport efflux - Active transport – drug transporters - Facilitated transport influx favors absorption - Facilitated transport efflux works against absorption - Local blood flow - The amount of drug entering into the blood per minute (rate) and the extent (total amount) of drug absorption is affected by the local blood flow - Decreased local blood flow decreases the rate of drug absorption (and vice versa) - Also depending on the type of circulatory alteration, a decreased local blood flow decreases the extent of drug absorption (and vice versa) - The chemical nature of the drug (physicochemical properties) - Lipid solubility - The MORE lipid soluble the drug, the FASTER the absorption (as cell membranes allow mvt) - Molecular size - The SMALLER the drug the EASIER the absorption - Ionization state - Total drug has an ionized (charged) and non-ionized (uncharged) fraction, depending on the PKa of the drug (drug’s property) and the pH of the environment Only a fraction of the molecules will be able to pass the membrane → **Only uncharged molecules will cross a cell membrane**  - Route of drug administration **KNOW this table! Route Advantage Disadvantage Enteric No special equipment Slow onset of action Several factors can alter the process of drug absorption +/- food, pH of GIT, intestinal flora, gastric emptying, intestinal transit time – diarrhea, potential drug interactions / precipitation, etc. Ex: liquid in NG tube of horse - 60+ mins Respiratory Rapid drug absorption because of a large, highly perfused Some drugs can cause irritation of the airways surface area and thin epithelial barrier Topical Relatively safe Abraded or damaged epithelium could allow the Easy access absorption of unsafe amounts of the drug Some drugs are not absorbed (e.g. some antiparasites) Slow absorption which leads to slow onset of drug Ex: Fentanyl = well-absorbed from skin action Ex: Fentanyl patches – 24-36 hrs to reach peak concentration  Mucosal Rapid onset of action Intravenous Rapid onset of action Sterile conditions No absorption phase! If not given properly can cause local tissue damage Intramuscular Usually complete absorption The volume of the formulation could be a limitation Watch out for changes in blood flow in resting vs If not given properly can cause local tissue damage exercising muscle Subcutaneous Usually complete absorption Usually slower onset than IM The volume of the formulation could be a limitation If not given properly can cause local tissue damage **IM and SQ faster than oral absorption but slower than IV - Availability of the drug - The pharmaceutical formulation of the drug - Same drug formulated a different way? Can be linked to difference in pharmacological effect - Rate of absorption and effect may differ - Formulation is used to control how fast absorption is To be absorbed drugs need to enter into solution: The type of formulation and design of the formulation → rate and extent of drug entering into solution → rate and extent of drug absorption → pharmacological effect - A drug needs to be dissolved into a solution for it to be absorbed Drug Distribution (D) - The movement of drug molecules from systemic circulation to the organs, and from organs back to systemic circulation (to eventually be eliminated by liver or kidneys) - Drug molecules NEED to go back to the systemic circulation Reversible transfer of drug molecules from one location to another within the body Why is the process of drug distribution important?  - Drug distribution influences the drug concentration in tissues → - Onset of action - Intensity of effect - Extent of effect - Adverse effects Mechanism of drug distribution - Influx and efflux transporters - Efflux transport is a mechanism responsible for moving compounds out of cells - The direction of the movement could be: - From a cell to an eliminating duct (e.g. bile, renal tubules) - From an organ cell to the interstitial fluid - From an endothelial cell to the capillary lumen (e.g. P-glycoprotein in blood brain barrier) - The impact of a change of the activity (inhibition or enhancement) of an efflux transporter on plasma concentrations will depend on the location of the efflux transporters Extent of drug distribution - Note that the concentration of a drug is not necessarily the same in all body organs - Some organs may accumulate a greater amount of drug than others - A drug may enter faster into some organs (e.g. brain) than into others (e.g. anesthetics and fat) Factors that affect the rate and extent of drug distribution: - Anatomical barriers (and transporters) - Some drugs affect the transport of other drugs (drug to drug interaction) - Can add a drug that decreases transporter rates OR one that may be a transporter inducer - There are genetic differences for transporter rates - Facilitated transport influx transporters – favor distribution into tissues - Facilitated transport efflux transporters – against distribution into tissues - **KEY POINT: Transporters are involved in distribution, and can be affected by other drugs and genetics! - The chemical nature of the drug - Lipid solubility – the more lipid soluble the drug, the faster the absorption and distribution - Molecular size – the smaller the drug the easier the absorption and distribution  - Ionization state – depends on PKa of the drug and pH of environment - PKa of drug = pH at which the drug is 50% ionized and 50% non-ionized - At any given time, there will be a fraction of the drug that is ionized (charged), and a fraction of the drug that will be non-ionized (uncharged) - Only uncharged molecules will cross a cell membrane! - The ionized form of a molecule will not cross membranes because of its low lipid solubility - **Acidic environments trap bases, whereas alkaline environments trap acids! - Ratio of the blood flow to tissue mass (tissue perfusion rate) - Blood carries drug away from the absorption site to the other tissues of the body (distribution) - The greater the blood flow, the faster the drug distribution - HIGH (highly perfused): CNS, liver, lung, gut, kidney, heart, exercising muscle - LOW: skin, fat, bone, resting muscle - The drug will enter faster in highly perfused tissues - More blood flow → more molecules going into organs - Plasma and tissue protein binding - At any time there is a fraction of drug molecules that are free, and a fraction bound by proteins - Only free molecules can pass cell membranes - Once they pass, some are free and some are bound - Only free molecules can interact with receptors! Rate and extent of drug absorption, AND rate and extent of distribution, affect the plasma concentration → drug effect Drug Distribution: Unique Situations - Shock – circulatory collapse that will slow drug elimination and alter drug distribution - Excitement/Exercise – increase blood flow to muscles may modify the patterns of drug distribution - Neonates - Lower extent of plasma protein binding - Larger water content → **dose in general is higher – same amount of drug will be diluted! - e.g. Foals need a larger dose of gentamycin - Pregnancy - Accumulation of drugs in the fetus - Ascites - Greater water content in the abdomen - Toxicity of lipid-soluble drugs - A dose based on body weight may result in higher drug concentrations in blood (because lipid-soluble drugs do not enter water) - Excess molecules in the blood may migrate to other tissues → leading to toxic effects - Obesity - Highly lipophilic drugs will tend to accumulate in fat - Toxicity of water-soluble drugs - A dose based on body weight may result in higher drug concentrations in blood (because water-soluble drugs do not enter fat) - Excess molecules in the blood may migrate to other tissues → leading to toxic effects Drug Distribution: Review Drug Metabolism (M) Drug elimination is the irreversible removal of a drug from the body by any routes of elimination - Biotransformation: the process by which a drug is chemically converted in the body to a metabolite - Occurs via enzymatic systems - Note that enzymes have a maximum capacity - As body metabolizes a drug, it can create inactive and toxic metabolites - Very complex; outcome depends on drug and enzymatic systems - Excretion: the removal of drug and metabolites from the body Transformation of the structure of the drug results in → hydro-soluble (polar) metabolite, OR → lipid-soluble molecule (difficult to eliminate) Types of Metabolic Reactions Types of Phase I Types of Phase II Reactions Reactions Oxidation** Glucuronidation** Reduction Acetylation Hydrolysis Methylation Sulfation Conjugation of amino acids (glycine) Conjugation of glutathione 4 Options: 1. Drugs that undergo only Phase I 2. Drugs that undergo Phase I and then Phase II 3. Drugs that undergo only Phase II 4. Drugs that are not biotransformed Oxidation - Reaction catalyzed by Cytochrome P450 (CYP) ** Anatomical sites for biotransformation: - Kidney - Lungs - GI tract - Circulation - Microbiota - Liver** – most important; has highest amount of enzymes Activity of enzymes is the main factor affecting elimination. Increased drug biotransformation: - An inducer can accelerate the inactivation of a drug, leading to a lower drug concentration - Molecule that induces enzyme activity Decreased drug biotransformation: - An inhibitor of the enzymatic system can decrease the inactivation of a drug, leading to higher concentrations - May translate to toxic effects Kinetics of biotransformation** Biotransformation: → first order process → when enzymatic system does not reach its maximum capacity → the rate of biotransformation increases proportionally to the concentration of the drug → zero order process → when the enzymatic system does reach its maximum capacity → the rate of biotransformation does not increase proportionally to the concentration of the drug First order process Zero order process Non saturation of enzymatic system Saturation of enzymatic system - Proportional changes of the concentration resulting in - Lack of proportional changes of the concentration resulting predictable changes in plasma concentration in unpredictable changes in plasma concentration Advantage of proportionality: example If a dose is increased 2x… → when there is a dose or concentration proportional mechanism (linear, predictable, first order) → plasma concentration increases 2x → drug effect increases → when there is a lack of dose or concentration proportional metabolism (non linear, non predictable, zero order) → plasma concentration increases ?? → drug effect ??? Variability in drug biotransformation - There is variability in drug biotransformation among species even within the same species and breeds - Why is there variability? - Because species use different enzymes to biotransform (for some drugs) - Because enzymes do not always work the same way in all species (may be faster, slower, or no biotransformation) Induced or genetically based variability in drug metabolism can result in 4 different types of drug metabolizers: 1. Ultra-rapid metabolizers a. Too rapid drug metabolism b. No drug response at ordinary dose c. Toxicity by active metabolites d. Often need higher dose 2. Extensive metabolizers a. Expected drug response 3. Intermediate metabolizers a. May experience some or a lesser degree of the consequences of the poor metabolizer 4. Poor metabolizers a. Too slow or not drug metabolism b. Too high drug concentrations at the ordinary dose c. High risk of toxicity d. Low pharmacologic response due to less active metabolites e. Often need lower dose Common toxicity in cats:  - Over the counter drugs - Aspirin, acetaminophen (e.g. Tylenol), ibuprofen - Why? - Cats have a slower capacity to glucurono-conjugate → resulting in higher drug concentration in plasma Why do enzymes not always work the same way in all species? - Because differences in the structure and/or availability of the metabolic enzymes First pass effect - When a fraction of the dose administered by any route can be metabolized before reaching the systemic circulation - Note that, in pharmacokinetics, the portal vein system is not considered part of the systemic circulation - Consider especially for drugs administered through the oral route - Oral → enterocytes → portal vein system → liver → captures some molecules; elimination of some molecules before they enter systemic circulation **First pass metabolism is important when the metabolism of a drug is altered (induced or inhibited) There are 2 ways that first pass effect occur: 1. Via biotransformation 2. Via excretion Fraction considered absorbed can be more or less depending on how the liver biotransforms the molecules during first pass effect; can be reduced, normal, or increased Drug Excretion Kidney Excretion 1. Filtration 2. Secretion 3. Reabsorption Drug Filtration A fraction of the molecules present in the circulatory system will reach the kidney - A constant fraction of the total drug molecules that reach the kidneys will be filtered through the glomerulus wall, entering into the tubular system - It is a passive process Drug Secretion Drug molecules are taken up by membrane transport proteins and then delivered to the lumen of the tubules  - Many drugs need transporters to be excreted (ex: furosemide, NSAIDs) Some drugs affect the transport of other drugs (drug to drug interaction) - May favor excretion - May be against excretion Drug Reabsorption Following drug filtration as well as secretion, some drug molecules can be reabsorbed into the circulatory system - It is a passive process; similar to passive diffusion Factors that affect the rate of drug elimination Biliary Excretion - Water-soluble (polar) - High molecular weight molecules (because molecule has been conjugated) - Transport mediated (active process) - Transporter can be induced or blocked, and subsequently alter plasma concentration - An inhibitor of a transporter can decrease the excretion of a drug, leading to higher plasma concentrations Enterohepatic recycling Clinical relevance: - The effect of some drugs depends on a normal enterohepatic recycling, because it influences the disposition of the drug in the body The EHR can be altered if your patient has: - Biliary disease - Alteration of biliary drug transporters - Liver disease - Small intestine disease You will need to determine if the drug should be changed or the dosage regimen optimized (modify dose and/or modify dose interval) Elimination via respiration - Important for anesthetic gasses - More details in anesthesiology Mammary excretion - Bases better than acids - Milk pH ~6.8 vs plasma ~7.4 - May result in significant neonatal exposure Sweat and saliva - Not significant pathways, but drugs do appear there - May be of concern when certain drugs are used (e.g. chemotherapeutics, which are really potent) How can we use information about drug excretion? - To design treatment plans - Avoid drugs - Select drugs Clinical application: - If a patient has a urinary tract infection, which kind of drug should be used? - Select a drug excreted by urine, like Gentamicin - 100% eliminated by kidneys - If a patient has a urinary infection and kidney injury? - Select a drug eliminated by urine that is not nephrotoxic Pharmacokinetic Parameters I **PK parameters are in the insert of drug products – at the end of this topic, I should be able to explain and use these parameters! The study of a drug’s PK involves several parts: Step 1: drug administration Step 2: blood sampling over time Step 3: determination of plasma drug concentration Step 4: pharmacokinetic analysis (application of mathematical models to describe the time course of drug concentrations in the body → these models generate the PK parameters that map out the time course of drug concentrations in the body) If the process of ADME changes or is variable (e.g. due to disease, different formulation, different route of administration) → the time courses of the drug concentration in the body changes → reflected on PK parameters Pharmacokinetic Parameters - Dose-dependent PK parameters - Cmax - AUC - Dose-independent PK parameters - Tmax - Bioavailability - Clearance - Volume of drug distribution - Half-life Under linear PK conditions… Dose-dependent PK parameters - The value of these PK parameters changes when the dose or frequency of doses changes Dose-independent PK parameters - The value of these PK parameters does not change when dose or frequency of doses changes - But may change if there are changes in ADME **Key take-home message: - If the process of ADME changes (e.g. due to disease, different formulation, different route of administration) → the time courses of the drug concentration in the body changes → as a result, the value of dose-dependent PK and dose-independent PK parameters could change Pharmacokinetic parameters associated with drug absorption AUC = area under the curve; reflects extent of drug exposure Tmax = time after administration when Cmax is obtained Correlation Cmax / drug effect and AUC / drug effect - Dose correlates with Cmax and AUC, which correlates with intensity, extent, and duration of the pharmacological effect - Higher Cmax and AUC? → higher and longer effect Time to maximum drug concentration (Tmax) Rate of absorption = Ra = amount of drug absorbed per unit of time Rate of elimination = Re = amount of drug eliminated per unit of time Clinical importance of Tmax: - Tmax can be used to predict when the maximum drug effect will occur - Important: drug response often lags behind plasma drug concentration Time of onset of effect depends on several factors: - Pharmacokinetics-rate limited response - Slow absorption or altered drug absorption due to changes in transit time or disease - Delay in the metabolism of an inactive drug (prodrug) into an active metabolite - Slow distribution to the active site (when a slow equilibrating tissue is also the target organ) Increasing the dose or using a loading dose → shortens the time of onset of effect - By shortening the time required to achieve the critical concentration at the site of action Reminder: IV administration = no absorption - So Tmax occurs right after administration Bioavailability - Refers to the rate and extent of drug absorption after extravascular (EV) drug administration - Fraction of the dose that is absorbed **Doubling the dose, but not getting double the drug in the system! F is an important parameter - Used to calculate dosage when the drug is administered by an EV dose (EV dose = IV dose / F) **Must compensate Factors that affect drug bioavailability - An increment in the bioavailability of a drug could be the result of: - Liver disease - Decrease in the first-pass effect of drugs administered orally - Inhibition of enzymes due to the co-administration of drugs - Anything that affects the absorptive environment can affect drug bioavailability - A decrease in the bioavailability of a drug could be the result of: - Induction of enzymes due to the co-administration of other drugs - Compounded formulations - Manipulation of the pharmaceutical formulations  - Gastrointestinal disease (for oral administration) - Diarrhea - Dehydration (in particular for drugs administered by the subcutaneous route, due to a decrease in peripheral blood flow) Clearance A primary pharmacokinetic parameter that reflects drug elimination from the body - Formal definition: rate of drug elimination scaled by (divided by) plasma concentration - Operational definition: volume of the plasma totally cleared of drug per time unit The larger the value, the faster the elimination. Clearance is probably the most important PK parameter because it is the ONLY one that describes drug elimination It remains constant under linear conditions and is dose independent If clearance is altered, the plasma concentration and several PK parameters will be altered - Many parameters are based on / affected by clearance