PharmacoKINETICS Class (3 per) PDF

11/6/24 Introduction to Pharmacology: PharmacoKINETICS Kelly Elmore, DNP, APRN-CRNA Mary Baldwin University Advanced Pharmacology for Anesthesiology Practice I Spring Semester 1 Pharmacology Goals: prevent, cure, control disease Overview...

11/6/24 Introduction to Pharmacology: PharmacoKINETICS Kelly Elmore, DNP, APRN-CRNA Mary Baldwin University Advanced Pharmacology for Anesthesiology Practice I Spring Semester 1 Pharmacology Goals: prevent, cure, control disease Overview Introducing: Lorem ipsum Anesthesia: Understanding the problems Response to changes in physiologic status Project objective Sedation, general anesthesia, amnesia Target audience Analgesia Market Muscletrends relaxation Prevent Cycle diagramcomplications Project timeline Safety 2 Pharmacology PharmacoKINETICS PharmacoDYNAMICS Study of what a drug does to the body Study of what the body does to a drug Relationship between effect site Relationship between dose and plasma concentration and clinical effects concentrations PharmacoBIOPHASICS Affected by drug absorption, ○ Specific area or effect site (biophase) distribution, metabolism, elimination where drug engages with receptor for clinical effect 3 1  11/6/24 Pharmacokinetics ABSORPTION DISTRIBUTION METABOLISM EXCRETION 4 Quick Review ROUTES ANSWER First-pass elimination by the liver reduces the efficacy of many drugs taken by this route BONUS!! is used This route bypasses the intestine and liver. Examples: NTG and buprenorphine This routedrugs to inject This route is commonly used for the patient without IV access. It allows for o directly int al drug precipitation in the area and sustained dose release pin cerebros fluid. The most common parenteral route. Avoids the GI tract and 1st pass metabolism, delivered straight to the effect site A route with richly vascular mucosa. Effects may be local or systemic and avoid 1st pass metabolism. Commonly used in peds, drug abusers Common route for drug delivery in general anesthesia. Minimizes systemic effects when used for patients with pulmonary pathology A parenteral route with a slower onset than IV. Vasoconstrictors may be administered here to reduce the area of action of another drug 5 6 2  11/6/24 ABSORPTION https://www.pharmacologyeducation.org/clinical-pharmacology/clinical-pharmacokinetics 7 Absorption Drug transfer from administration site to blood stream ○ Rate & efficiency dependent on route Absorption is complete for _______________________________ drugs Partial absorption for other routes Gastrointestinal transport ○ Passive diffusion: higher concentration to lower (down gradient) ○ Active transport: carrier proteins Energy-dependent process to move drug against concentration gradient (low to high) 8 pH & Ionization Typically, it is the nonionized form of the drug which is Ionization: process of gaining a positive or negative charge pharmacologically active! ○ Acid: proton donor ○ Base: proton acceptor ○ Dependent on pH of solution and pKa of drug When pH and pKa are the same, half of drug ionizes ○ Affects ability to diffuse through lipid membrane Nonionized (uncharged molecule) Lipid soluble, free, unbound 9 3  11/6/24 pH & Ionization 75% 83% Lorem Ipsum Lorem Ipsum Lorem Ipsum Lorem Ipsum 10 pH & Ionization Weak acids or weak bases ○ Uncharged acid HA donates H+ (proton) forming the charged anion, _______________ ○ Uncharged base B accepts H+ (proton) forming charged ___________________ pKa (dissociation constant) ○ Measure of strength of interaction of compounds with a proton ○ Lower the pKa, stronger the acid 11 pKa & pKb 75% 83% Lorem Ipsum Lorem Ipsum Lorem Ipsum Lorem Ipsum 12 4  11/6/24 pKa & Ionization 75% 83% Lorem Ipsum Lorem Ipsum Lorem Ipsum Lorem Ipsum 13 Ionization & Transport Uncharged HA acid form readily passes Uncharged B base form readily passes Denotes _____________________________ reactions – acids & bases change forms with their conjugates ○ pH at the absorption site ○ Strength of the weak acid or base ○ pKa of the drug Acids dissolve and diffuse more readily into acidic solutions with pH lower than the drug’s pKa Bases dissolve and diffuse more readily into basic solutions with pH greater than drug’s pKa 14 Drugs reach a distribution equilibrium once the lipid soluble (permeable) form achieves an equal concentration throughout compartments! Ionization & Transport 75% 83% Lorem Ipsum Lorem Ipsum Lorem Ipsum https://slideplayer.com /slide/16421011/ 15 5  11/6/24 Ion Trapping 16 Ionized ~VS~ Unionized _____________________________ ______________________________ ○ Soluble in water ○ Solubility in lipids Pharmacologically not active Pharmacologically active No diffusion across: Easy diffusion across: ○ Blood brain barrier ○ Blood brain barrier ○ GI tract ○ GI tract ○ Placenta ○ Placenta Renal excretion Hepatic metabolism 17 What Happens When… Add an acid to a basic solution? Add a base to an acidic solution? Proton donation! Proton acceptance! Acidic drug becomes highly Basic drug becomes highly ionized ionized Add a base to a basic solution? Add an acid to an acidic solution? Both want to accept protons Both want to donate protons No proton donors! No proton acceptors Drug remains unprotonated and highly unionized Drug keeps protons and is highly unionized 18 6  11/6/24 Factors of Absorption Route of administration Blood flow to absorption site Heat, vasodilation Vasoconstriction Surface area available Drug solubility Courtesy of Handwritten Tutorials. https://www.youtube.com /watch?v=pW W -aq7iSa0 19 Bioavailability Drug fraction that reaches systemic circulation Chemically unchanged drug must reach the circulation Influencing factors ○ Route of administration ○ First-pass hepatic metabolism ○ Drug solubility - aqueous solutions, lipophilic ○ Chemical stability and formulation of the drug 20 Quick Review 21 7  11/6/24 DISTRIBUTION https://biology-forums.com/index.php?action=gallery;sa=view;id=19562 22 Distribution Process by which drug leaves the area of administration (most concentrated form) and enters the plasma (diluted concentration) and cells/tissues (even more dilution!) Influencing factors ○ Blood flow to tissues ○ Capillary permeability ○ Chemical structure of the drug ○ ___________________________________________________ (plasma and tissues) 23 Molecular Size Size matters ○ Smaller - facilitates lipid barrier crossing ○ Weight > 100 - 200 does not cross Active vs passive transport revisited ○ Energy requirement ○ Speed of drug transfer ○ Carriers and concentration gradients 24 8  11/6/24 Protein Binding Drug molecules enter plasma and bind plasma proteins ○ ___________________________________ ○ Lipoprotein ○ Glycoprotein (eg, alpha-1-acid GP) ○ ⍺, β globulins Bound drug is ‘trapped’ in plasma, _________________________ Free drug can freely enter tissues (distributes) Free, unbound drug pharmacologically active https://biology-forums.com/index.php?action=gallery;sa=view;id=19564 25 Binding to Albumin Binding capacity – low vs high Affinity ○ Strongest – anionic drugs (weak acids), hydrophobic ○ Weakest – basic and neutral drugs, hydrophilic Competition ○ High affinity for albumin? ○ Free drug displacement 26 Binding to Albumin What are the anticipated effects in…. 27 9  11/6/24 Compartments Courtesy of Handwritten Tutorials. https://www.youtube.com/watch?v=6erefsWCVxg 28 2-Compartment Model: Answer Quick Central vs Peripheral? Review Lungs Endocrine glands BONUS!! Skin Which compartment Brain includes the kidneys? Fat What about the liver? Muscle Heart 29 (Apparent) Volume of Distribution Vd The theoretical fluid volume necessary to hold the same concentration of drug which exists, unbound (free) in the plasma and interstitial fluid ○ Tissue drug distribution ○ Greater the Vd, the larger the theoretical volume in the tissues compared to the volume of drug would occupy in the plasma ○ Assumes the drug distributes and equilibrates instantly ○ Assumes the drug is not metabolized, bio-transformed, or eliminated first 30 10  11/6/24 Volume of Distribution (Vd) A p e x A n e s th e s ia P h a r m a c o lo g y : V o lu m e o f D is tr ib u tio n 31 Volume of Distribution Vd used to calculate amount of drug to achieve desired plasma concentration Larger Vd → larger loading doses ○ 100% (= 1) bioavailability intravenous route ○ Dose given to achieve certain Cp https://www.youtube.com/watch?v=0IWMlf7b1M4 dependent on route 32 Vd & Equilibration Desired concentration at effect site ○ Plasma vs the effect site ○ Affects bolus (load) dosing, infusion kinetics Target controlled infusion (TCI) ○ Allows dosing based on plasma and effect site algorithms https://derangedphysiology.com/main/cicm-primary-exam/required- reading/pharmacokinetics/Chapter%203.3.3/effect-site-equilibration ○ Decreases infusion rate regularly to account for uptake and saturation of compartments 33 11  11/6/24 Volume of Distribution Vd exceeds total body water = __________________________________________ For example, > 42 L in 70 kg person Higher dose required to achieve goal plasma concentration (Cp) Propofol (~ 4.5 L/kg) Vd less than total body water = HYDROPHILIC For example, < 42 L in 70 kg person Lower dose required to achieve Cp Neuromuscular blockers (rocuronium ~ 0.08 L/kg) 34 Volume of Distribution Influencing Factors Vd influenced by… ○ Characteristics of drug (molecular size, ionization, protein binding) ○ Characteristics of patient (pregnancy, burns, liver disease) eg, propofol Vd approximately double in burn patients ○ Elimination Drug leaves plasma compartment and lost from body ○ Distribution between compartments (uneven) Vd influences… ○ Elimination Dependent on blood flow and fraction of drug present in plasma (Cp) Increasing Vd reduces drug in plasma, increasing half-life 35 MemoryMaster Knowledge Check Define volume of distribution. Drug diffusion across a membrane is proportional to what factors? Valley Anesthesia.(2023). answers Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 36 12  11/6/24 MemoryMaster Knowledge Check What is the most important plasma protein for drug binding? Degree of protein binding is dependent upon what primary factor? Which patients would have the greatest alterations? Valley Anesthesia.(2023). answers Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 37 MemoryMaster Knowledge Check Drugs absorbed by the gastrointestinal tract must first pass through which organ before reaching systemic circulation? What happens in the organ above and what is the term for this effect? Valley answersAnesthesia.(2023). Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 38 METABOLISM 39 13  11/6/24 Metabolism Alters chemical structure of molecule Pharmacologically active, lipid-soluble drug → __________________________________________ Exceptions ○ Active metabolites (eg, morphine-6-glucuronide) Similar therapeutic and side effects as parent drug ○ Prodrug (eg, fospropofol, codeine) Parent drug is inactive Metabolite is pharmacologically active drug Sites = liver, plasma, kidneys, lungs, GI tract https://www.wisegeek.com/what-is-cafestol.htm 40 Modification Elimination Increases water solubility Drug transportation (polarity) across membranes Mostly CYP450 enzymes ATP-dependent carrier May be excreted or proteins prepped for phase II Kidney, liver, GI tract Conjugation Increases H2O solubility Common substrates: glucuronide, glycine, acetic acid, sulfuric acid, methyl Phases of Metabolism 41 Phase I Pathways 42 14  11/6/24 Phase II Pathways 43 Microsomal Enzymes Responsible for biotransformation in the liver Microsomes = endoplasmic reticulum fragments from tissue breakdown ○ Contains cytochrome = iron-containing heme bound to protein ○ P-450 = peak absorption at 450 nm when reacting with carbon monoxide CYP-450 = mixed-function oxidase system ○ Both oxidation and reduction steps 44 CYP Enzymes Cytochrome P450 family ○ Membrane-bound proteins (smooth hepatic ER) ○ Also found in lungs, kidneys, skin, adrenals, GI tract mucosa ○ Most important mechanism* ○ Phase I (+/- some phase II reactions) ○ ________________________________________ 50% of drugs used in anesthesia Fentan(-ils), some benzodiazepines, some locals ○ CYP 2D6 Codeine, oxycodone, hydrocodone 45 15  11/6/24 Enzyme Induction VS. Inhibition Apex Anesthesia. Pharmacology I: Pharmacokinetics (P450 Enzymes) 46 Kinetics of Metabolism 47 Plasma Metabolism Hydrolysis common ○ H2O molecule to break ester bond Plasma enzymatic reactions ○ Pseudocholinesterase, nonspecific esterases, alkaline phosphatase ○ No enzymatic induction ○ Pseudocholinesterase deficiency ________________________________________________________ ○ Spontaneous chemical elimination reaction ○ Body pH and temperature 48 16  11/6/24 Plasma Metabolism Apex Anesthesia. Pharmacology I. Metabolism in the Plasma. Apexanesthesia.com 49 ELIMINATION 50 Elimination VS. Excretion Process by which drug is removed from the plasma vs. the body Routes ○ _________________________________ (primary) ○ Liver Metabolism Excretion into bile ○ Intestine ○ Lungs ○ Organ-independent elimination (eg, Hofmann, plasma esterases) ○ Breast milk 51 17  11/6/24 https://www.sciencedirect.com/topics/immunology-and-microbiology/drug-excretion 52 Clearance Volume of plasma completely cleared of drug per unit of time Efficiency of drug delivery (blood flow) & drug removal (extraction) https://www.slideshare.net/HadeelSalah/clearance-mechanism-biopharmaceutics 53 Clearance Directly related to ○ Organ blood flow ○ ______________________________ – fraction of drug irreversibly removed from the blood flow entering the clearing organ ○ Drug dose Indirectly related to ○ Drug half-life ○ Drug concentration in central compartment 54 18  11/6/24 Hepatic Extraction Ratio Extraction ratio = arterial concentration - venous concentration arterial concentration High extraction ratio (> 70%) ○ Proportional to change in ________________________________________ ○ Metabolism & clearance are “flow-limited” (flow dependent) ○ HBF greater than enzyme activity ○ Dependent on free (unbound) drug available ○ Propofol, ketamine, lidocaine, bupivacaine, fentanyl, morphine, metoprolol, nitroglycerin 55 Hepatic Extraction Ratio Low extraction ratio (< 30%) ○ Capacity of the liver to extract and metabolize the drug Liver disease, enzyme inhibition decrease capacity Changes in protein binding affect clearance ○ Mostly independent of liver blood flow ○ Metabolism and clearance are “capacity-limited” (capacity dependent) ○ Rocuronium, lorazepam, methadone, thiopental, warfarin, phenytoin Intermediate extraction ratio - midazolam, vecuronium, methohexital Oral administration - high ER drugs undergo first pass metabolism 56 Renal Elimination & Excretion Volume of plasma cleared of drug ○ Renal blood flow multiplied by renal extraction ratio Determined by ○ Drug molecule’s _______________________________________ ○ pH of glomerular filtrate ○ Hydrophilic - excreted unchanged ○ Lipophilic - biotransformed (water soluble) 57 19  11/6/24 Renal Elimination & Excretion Glomerular filtration ○ Free drug enters Bowman’s capsule and filtrate Proximal tubular secretion ○ Drug escaping glomeruli enters efferent arterioles ○ Active transport systems secrete drug into tubular filtrate Distal tubular reabsorption ○ Concentration in tubules exceeds vascular levels ○ Unionized drug may be reabsorbed Urine pH Urine flow rate 58 Renal Elimination & Excretion https://clinicalgate.com/pharmacokinetics-pharmacodynamics-and-drug-interactions/ 59 Renal Elimination & Excretion Urine pH ○ Acidic urine Reabsorption of acidic drugs Excretion of basic drugs Ammonium chloride, cranberry acidifies ○ Basic/alkaline urine Reabsorption of basic drugs Excretion of acidic drugs Sodium bicarbonate, acetazolamide alkalizes 60 20  11/6/24 https://derangedphysiology.com/main/cicm-primary-exam/required- reading/pharmacokinetics/Chapter%203335/renal-clearance 61 Renal Elimination & Excretion Renal insufficiency/failure reduces elimination of unchanged (minimally metabolized) drugs and active metabolites ○ Toxicity risk ○ Proportional dose or interval reductions > 50% drug renally cleared Renal function decreased < 50% normal ○ Monitoring of drug levels w/narrow therapeutic index Drug-drug interactions may alter renal clearance 62 Half-LIFE (t1/2) Time required to __________________________________________________________________ following rapid IV injection Volume of distribution directly related to half-life Clearance indirectly related to half-life Approximately ________ half-lives for ~97% elimination 63 21  11/6/24 Half-LIFE (t1/2) https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/286/half-life https://www.ncbi.nlm.nih.gov/books/NBK554498/figure/article-22492.image.f1/ 64 Half-LIFE (t1/2) Increased by ○ Decreased renal blood flow (eg, decreased cardiac output) ○ Displacement of drug from albumin ○ Decreased extraction ratio ○ Decreased metabolism 65 Clearance is directly proportional to: A. Half-life B. Blood flow to organ clearing the drug C. Concentration in the central compartment D. Extraction ratio Quick Review 66 22  11/6/24 Injection & Infusion Kinetics http://www.rxkinetics.com/pktutorial/1_5.html 67 Injection & Infusion Kinetics Cp primarily influenced by ○ Distribution ○ Redistribution ○ Metabolism ○ Excretion 68 One-Compartment Model Instantaneous drug mixing into one homogenous compartment Theoretical rapid distribution and equilibration of drug with all tissues Drug input determined by dosage regimen (bolus intervals, rate of infusion) Drug output determined by constant elimination rate Example: aminoglycosides http://www.rxkinetics.com/pktutorial/1_5.html 69 23  11/6/24 Multi-Compartment Models Theoretical compartments for drug movement Drug distributes and undergoes elimination Two- and three- compartment models ○ Distribution along _____________________________________________ from central compartment (plasma) to various peripheral compartments (tissues) Distribution phases ○ Rapid ○ Slow ○ Terminal 70 Two-Compartment Models Rapid IV bolus Steep slope of A = rapid reduction in Cp ○ Lipophilic drugs → larger Vd → steeper slope Flattened slope of B = redistribution & elimination ○ Redistribution - leaves tissues and re-enters plasma ○ Elimination process begins 71 Three-Compartment Models Drug movement dependent on: ○ Vd ○ Plasma and tissue concentrations ○ Rate constants (k) Speed at which drug molecule moves between compartments or is eliminated ○ Half-lives ○ Clearances https://www.researchgate.net/figure/Three-compartment-model-showing-the-various-compartments- and-their-associated-rate_fig2_279277879 72 24  11/6/24 Steady State Amount of drug entering body equals amount of drug being eliminated ○ = _________________________ plasma concentration Cp ○ Infusion rate or dosing interval must equal clearance (metabolism + elimination) Equilibration across body compartments 4 - 5 half-lives to reach steady state if given at regular intervals 73 Steady State http://.blogspot.com/2013/06/x.htmln-pharmacology 74 After administration of an IV drug which distributes into a one-compartment model, the patient’s plasma level is 6.25% of the original dose. How many half-lives have elapsed? Quick Review 75 25  11/6/24 Half-TIME Time it takes for 50% of drug to be removed from plasma during elimination ○ Measures a constant fraction of drug eliminated ○ Only applicable in 1-compartment models ○ VS. half-life 76 Context-Sensitive Half-Time Time required for Cp to decline by 50% following a steady- state IV infusion __________________________ of IV drug infusion = ‘context’ Distribution into peripheral compartments over time IV hypnotic recovery ○ > 50% decrease in Cp ○ Context-sensitive effect-site elimination https://behindthedrape.files.wordpress.com/2019/05/context-sensitive-half-time-diagram.jpg 77 Drug Z is eliminated by 1st order kinetics. You administered 100 mg and 50 mg has been metabolized after 2 hours. What is the total amount of drug metabolized after 4 hours? Quick Review 78 26  11/6/24 MemoryMaster Knowledge Check What is elimination half-time? How does elimination half-time change with increased Vd? How does elimination half-time change with increased clearance? Valley Anesthesia.(2023). answers Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 79 MemoryMaster Knowledge Check What is context-sensitive half-time and what is the “context”? What is a limitation of context-sensitive half-time? Valley answersAnesthesia.(2023). Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 80 MemoryMaster Knowledge Check A drug is eliminated by 1st order kinetics. Four grams are administered. Five hours later, two grams have been metabolized. After 10 more hours, how much more is metabolized? Valley Anesthesia.(2023). answers Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 81 27  11/6/24 MemoryMaster Knowledge Check A drug is eliminated by 1st order kinetics. 200 milligrams are administered. Half-life is 20 hours. How long will it take for the plasma concentration to fall to 50 milligrams? Valley Anesthesia.(2023). answers Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 82 MemoryMaster Knowledge Check A drug is eliminated by 1st order kinetics. 60 mg are administered. 15 mg remains after 12 hours. How much drug is eliminated in the next 12 hours? Valley answersAnesthesia.(2023). Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 83 MemoryMaster Knowledge Check What does it mean that alcohol is eliminated by zero-order kinetics? Adults metabolize about 10 g of ethanol per hour. How long will it take to metabolize 3 ounces of 80 proof vodka (1 oz = 10 g)? Valley Anesthesia.(2023). answers Memory for the student nurse Master:(33rd anesthetist Questions and ed.). P.110-111 84 28  11/6/24 END! 85 References https://www.khanacademy.org/test-prep/mcat/chemical-processes/stereochemistry/a/chiral-drugs https://slideplayer.com/slide/4727993/ https://www.slideshare.net/drmmprao1/ropivacane-a-new-break-through-in-regional-and-neuraxial-blockade https://basicmedicalkey.com/pharmacokinetics-10/ https://onlinehealtheducation.com/agonist-partial-agonist-antagonist-inverse-agonist/ https://www.sciencedirect.com/topics/chemistry/receptor-modulator https://en.wikipedia.org/wiki/Receptor_(biochemistry) https://www.youtube.com/watch?v=pWW-aq7iSa0 https://en.wikipedia.org/wiki/Volume_of_distribution https://www.pharmacologyeducation.org/clinical-pharmacology/clinical-pharmacokinetics 86 References https://www.youtube.com/watch?v=6erefsWCVxg https://www.youtube.com/watch?v=0IWMlf7b1M4 https://derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacokinetics/Chapter%203.3.3/effect-site- equilibration https://biology-forums.com/index.php?action=gallery;sa=view;id=19564 https://derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacokinetics/Chapter%203335/renal-clearance https://www.ncbi.nlm.nih.gov/books/NBK554498/figure/article-22492.image.f1/ https://derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacokinetics/Chapter%203.2.2/half-life https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223885/ https://www.researchgate.net/figure/Three-compartment-model-showing-the-various-compartments-and-their-associated- rate_fig2_279277879 https://sepia.unil.ch/pharmacology/index.php?id=72 https://academic.oup.com/bjaed/article/7/1/25/509187 87 29