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USMLE Pharmacology.indb 1MOY.CSAE2STEP1EPharmacologyLMSU NotesLecture201710/20/16 10:03 AM

MOY.CSAE2ELMSUUSMLE is a joint program of the Federation of State Medical Boards (FSMB) and the National Board ofMedical Examiners (NBME), neither of which sponsors or endorses this product.This publication is designed to provide accurate information in regard to the subject matter covered asof its publication date, with the understanding that knowledge and best practice constantly evolve. Thepublisher is not engaged in rendering medical, legal, accounting, or other professional service. If medicalor legal advice or other expert assistance is required, the services of a competent professional should besought. This publication is not intended for use in clinical practice or the delivery of medical care. To thefullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/ordamage to persons or property arising out of or related to any use of the material contained in this book. 2017 by Kaplan, Inc.Published by Kaplan Medical, a division of Kaplan, Inc.750 Third AvenueNew York, NY 1001710 9 8 7 6 5 4 3 2 1Course ISBN: 978-1-5062-0875-6All rights reserved. The text of this publication, or any part thereof, may not be reproduced in any mannerwhatsoever without written permission from the publisher. This book may not be duplicated or resold, pursuant to the terms of your Kaplan Enrollment Agreement.Retail ISBN: 978-1-5062-0839-8Kaplan Publishing print books are available at special quantity discounts to use for sales promotions,employee premiums, or educational purposes. For more information or to purchase books, please call theSimon & Schuster special sales department at 866-506-1949.Pharmacology.indb 210/20/16 10:03 AM

EditorsCraig Davis, Ph.D.Distinguished Professor EmeritusUniversity of South Carolina School of MedicineDepartment of Pharmacology, Physiology, and NeuroscienceColumbia, SCSteven R. Harris, Ph.D.Associate Dean for Academic AffairsProfessor of PharmacologyKentucky College of Osteopathic MedicinePikeville, KYMOY.CSAE2ELMSUContributorsManuel A. Castro, MD, AAHIVSDiplomate of the American Board of Internal MedicineCertified by the American Academy of HIV MedicineWilton Health Center (Private Practice)Wilton Manors, FLNova Southeastern UniversityClinical Assistant Professor of MedicineFort Lauderdale, FLLECOM College of OsteopathyClinical Assistant Professor of MedicineBradenton, FLLaszlo Kerecsen, M.D.Professor of PharmacologyMidwestern University AZCOMGlendale, AZBimal Roy Krishna, Ph.D., FCPProfessor and Director of PharmacologyCollege of Osteopathic MedicineTouro University, NVPharmacology.indb 310/20/16 10:03 AM

MOY.CWe want to hear what you think. What do you like or not like about the Notes?Please email us at medfeedback@kaplan.com.SAE2ELMSUPharmacology.indb 410/20/16 10:03 AM

ContentsSection I: General PrinciplesChapter 1: Pharmacokinetics . . . . . . . . . . . . . . . . . . .3Chapter 2: Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Chapter 3: Practice Questions . . . . . . . . . . . . . . . . . .29Section II: Autonomic PharmacologyChapter 1: The Autonomic Nervous System (ANS) . . . . . . . . . . . . . . . . . . . 39Chapter 2: Cholinergic Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Chapter 3: Adrenergic Pharmacology . . . . . . . . . . . . . . .55Chapter 4: Autonomic Drugs: Glaucoma Treatmentand ANS Practice Problems . . . . . . . . . . . . . . .65Chapter 5: Autonomic Drug List and Practice Questions . . . . . . . . 71Section III: Cardiac and Renal PharmacologyChapter 1: Diuretics . . . . . . . . . . . . . . . . . . . . . .83Chapter 2: Antihypertensives . . . . . . . . . . . . . . . . . . .91Chapter 3: Drugs for Heart Failure . . . . . . . . . . . . . . . .97Chapter 4: Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . 101Chapter 5: Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111Chapter 6: Antihyperlipidemics . . . . . . . . . . . . . . . . . 117Chapter 7: Cardiac and Renal Drug List and Practice Questions . . . . . . . 121vPharmacology.indb 510/20/16 10:03 AM

USMLE Step 1lPharmacologySection IV: CNS PharmacologyChapter 1: Sedative-Hypnotic-Anxiolytic Drugs . . . . . . . . . . . . . . . . . . . . . 133Chapter 2: Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137Chapter 3: Drugs Used for Depression, Bipolar Disorders,and Attention Deficit Hyperactivity Disorder (ADHD) . . . . 139Chapter 4: Drugs Used in Parkinson Disease and Psychosis . . . . . 143Chapter 5: Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149Chapter 6: Drugs Used in Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Chapter 7: Opioid Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159Chapter 8: Drugs of Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Chapter 9: CNS Drug List and Practice Questions . . . . . . . . . . . . . . . . . . . 165Section V: Antimicrobial AgentsChapter 1: Antibacterial Agents . . . . . . . . . . . . . . . . . 177Chapter 2: Antifungal Agents . . . . . . . . . . . . . . . . . .193Chapter 3: Antiviral Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197Chapter 4: Antiprotozoal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205Chapter 5: Antimicrobial Drug List and Practice Questions . . . . . . . . . . . . 207Section VI: Drugs for Inflam atory and Related DisordersChapter 1: Histamine and Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . 219Chapter 2: Drugs Used in Gastrointestinal Dysfunction . . . . . . . . 221Chapter 3: Drugs Acting on Serotonergic Systems . . . . . . . . . . 225Chapter 4: Eicosanoid Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Chapter 5: Drugs Used for Treatment of Rheumatoid Arthritis . . . . . 233viPharmacology.indb 610/20/16 10:03 AM

Chapter 6: Drugs Used for Treatment of Gout . . . . . . . . . . . 235Chapter 7: Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237Chapter 8: Drugs Used for Treatment of Asthma . . . . . . . . . . . . . . . . . . . . 239Chapter 9: Inflammatory Disorder Drug Listand Practice Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243Section VII: Drugs Used in Blood DisordersChapter 1: Anticoagulants . . . . . . . . . . . . . . . . . . .257Chapter 2: Thrombolytics . . . . . . . . . . . . . . . . . . . .261Chapter 3: Antiplatelet Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263Chapter 4: Blood Disorder Drug List and Practice Questions . . . . . 265Section VIII: Endocrine PharmacologyChapter 1: Drugs Used in Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271Chapter 2: Steroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277Chapter 3: Antithyroid Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283Chapter 4: Drugs Related to Hypothalamic and Pituitary Hormones . . . . 285Chapter 5: Drugs Used for Bone and Mineral Disorders . . . . . . . . . . . . . . 287Chapter 6: Endocrine Drug List and Practice Questions . . . . . . . 289Section IX: Anticancer DrugsChapter 1: Anticancer Drugs . . . . . . . . . . . . . . . . . .297Chapter 2: Anticancer Drug Practice Questions . . . . . . . . . . . . . . . . . . . . . 303Section X: ImmunopharmacologyChapter 1: Immunopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307Chapter 2: Immunopharmacology Practice Questions . . . . . . . . . . . . . . . 309viiPharmacology.indb 710/20/16 10:03 AM

USMLE Step 1lPharmacologySection XI: ToxicologyChapter 1: Toxicology . . . . . . . . . . . . . . . . . . . . . 313Chapter 2: Toxicology Practice Questions . . . . . . . . . . . . . . . . . . . . . . . . . . 319Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321viiiPharmacology.indb 810/20/16 10:03 AM

SECTION IGeneralPrinciplesPharmacology.indb 110/20/16 10:03 AM

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Pharmacokinetics1Learning Objectives Answer questions about permeation, absorption, distribution,biotransformation, elimination, and steady state Solve problems concerning important pharmacokinetics calculationsPharmacokinetic characteristics of drug molecules concern the processes ofabsorption, distribution, metabolism, and excretion. The biodisposition of a druginvolves its permeation across cellular membrane barriers.Drugadministration(IM, PO, etc.)Absorption into plasmaTissuestoragePlasmaDistribution to tissuesBound drugSites ofactionReceptorsFree drugDrug metabolism(Liver, lung, blood, etc.)Drug excretion(Renal, biliary,exhalation, etc.)Figure I-1-1. Drug Biodisposition3Pharmacology.indb 310/20/16 10:03 AM

Section IlGeneral PrinciplesPERMEATION Drug permeation is dependent on:–– S olubility. Ability to diffuse through lipid bilayers (lipid solubility)is important for most drugs; however, water solubility can influencepermeation through aqueous phases.–– Concentration gradient. Diffusion down a concentration gradient—onlyfree, unionized drug forms contribute to the concentration gradient.–– S urface area and vascularity. Important with regard to absorption ofdrugs into the systemic circulation. The larger the surface area and thegreater the vascularity, the better is the absorption of the drug.NoteFor Weak Acids and Weak BasesIonized Water solubleNonionized Lipid soluble Ionization–– M any drugs are weak acids or weak bases and can exist in either nonionized or ionized forms in an equilibrium, depending on the pH of theenvironment and the pKa (the pH at which the molecule is 50% ionizedand 50% nonionized)–– Only the nonionized (uncharged) form of a drug crosses biomembranes.–– The ionized form is better renally excreted because it is water soluble.Weak AcidR–COOH(crosses membranes)R–COO– H (better cleared)R–NH 3(better cleared)R–NH2 H (crosses membranes)Weak BaseGut bacteria metabolize lactulose tolactic acid, acidifying the fecal massesand causing ammonia to becomeammonium. Therefore, lactulose isuseful in hepatic encephalopathy.Weakbase80604020Weakacid–2–10 1pH-pKaRenal clearance of drugClinical Correlate% Nonionized form 2Figure I-1-2. Degree of Ionization and ClearanceVersus pH Deviation from pKa4Pharmacology.indb 410/20/16 10:03 AM

Chapter 1lPharmacokineticsIonization Increases Renal Clearance of Drugs Only free, unbound drug is filtered. Both ionized and nonionized forms of a drug are filtered. Only nonionized forms undergo active secretion and active or passivereabsorption. Ionized forms of drugs are “trapped” in the filtrate. Acidification of urine increases ionization of weak basesrenal elimination. increases Alkalinization of urine increases ionization of weak acids increasesrenal elimination.GlomerulusFree drug(unbound toprotein)ProximaltubuleIIFilteredNClinical CorrelateTo Change Urinary pH A cidify: NH4Cl, vitamin C, cranberryjuice A lkalinize: NaHCO3, aceta zolamide(historically) S ee Aspirin Overdose andManagement in Section VI.ExcretedNReabsorptionSecretionNBlood vesselI ionized drugN nonionized drugFigure I-1-3. Renal Clearance of DrugModes of Drug Transport Across a MembraneTable I-1-1. The Three Basic Modes of Drug Transport Across a quiredPassive diffusionDown gradientNoNoNoFacilitateddiffusionDown gradientNoYesYesActive transportAgainst gradient(concentration/electrical)YesYesYesBridge to PhysiologyIon and molecular transportmechanisms are discussedin greater detail in Section Iof Physiology.5Pharmacology.indb 510/20/16 10:03 AM

Section IlGeneral PrinciplesABSORPTIONAbsorption concerns the processes of entry of a drug into the systemic circulation from the site of its administration. The determinants of absorption are thosedescribed for drug permeation. Intravascular administration (e.g., IV) does not involve absorption, andthere is no loss of drug. Bioavailability 100% With extravascular administration (e.g., per os [PO; oral], intramuscular[IM], subcutaneous [SC], inhalation), less than 100% of a dose may reachthe systemic circulation because of variations in bioavailability.Lag time time from administration to appearance in blood.Onset of activity time from administration to blood level reaching minimal effective concentration (MEC).Time to peak time from administration to Cmax.LagDuration of action time plasma concentration remains greater than MEC.Time to peakOnset ofactivityPeak levelp t io ntmax time at which Cmax occurs.CmaxMinimum effectiveconcentrationA b sorCmax maximal drug level obtained with the dose.Plasma drug concentrationPlasma Level CurvesEltmaximin ati o nTimeDuration of actionFigure I-1-4. Plot of Plasma Concentration Versus Time6Pharmacology.indb 610/20/16 10:03 AM

Chapter 1lPharmacokineticsBioavailability (f)Measure of the fraction of a dose that reaches the systemic circulation. By defin tion, intravascular doses have 100% bioavailability, f 1.Plasma drug concentrationIntravascular dose(e.g., IV bolus)AUCPOf AUCIVAUC: area under the curveExtravascular dose(e.g., oral)PO: oralIV: intravenous bolusAUCIV: horizontally striped areaAUCPO: vertically striped areaTimeFigure I-1-5. Area Under the Curve for anIV Bolus and Extravascular DosesFirst-Pass EffectWith oral administration, drugs are absorbed into the portal circulation and initially distributed to the liver. For some drugs, their rapid hepatic metabolism decreases bioavailability—the “fi st-pass” effect.Examples: Lidocaine (IV vs. PO) Nitroglycerin (sublingual)BioavailabilityFirst ulationGI tractFigure I-1-6. Bioavailability and First-Pass Metabolism7Pharmacology.indb 710/20/16 10:03 AM

Section IlGeneral PrinciplesClinical CorrelateDISTRIBUTIONDrugs with high plasma proteinbinding and narrow therapeutic range,e.g., warfarin and phenytoin, are proneto drug interactions.Distribution is the process of distribution of a drug from the systemic circulationto organs and tissue. Conditions affecting distribution include: Under normal conditions, protein-binding capacity is much larger thanis drug concentration. Consequently, the free fraction is generally constant. Many drugs bind to plasma proteins, including albumin, with an equilib-rium between bound and free molecules (recall that only unbound drugscross biomembranes).Drug Protein(Active, free)Drug-Protein Complex(Inactive, bound) Competition between drugs for plasma protein-binding sites mayincrease the “free fraction,” possibly enhancing the effects of the drugdisplaced. Example: sulfonamides and bilirubin in a neonateThere are some special barriers to distribution: Placental: most small molecular weight drugs cross the placental barrier,although fetal blood levels are usually lower than maternal. Example:propylthiouracil (PTU) versus methimazole in pregnancy Blood–brain: permeable only to lipid-soluble drugs or those of very lowmolecular weight. Example: levodopa versus dopamineBridge to PhysiologyApproximate Vd Values(weight 70 kg) plasma volume (3 L) blood volume (5 L) e xtracellular flui(ECF 12–14 L) t otal body water(TBW 40–42 L)Apparent Volume of Distribution (Vd)A kinetic parameter of a drug that correlates dose with plasma level at zero time.DoseVd C0where C0 [plasma] at zero time his relationship can be used for calculating Vd by using the dose only if oneTknows C0. Vd is low when a high percentage of a drug is bound to plasma proteins. Vd is high when a high percentage of a drug is being sequestered in tis-sues. This raises the possibility of displacement by other agents; examples: verapamil and quinidine can displace digoxin from tissue-bindingsites. Vd is needed to calculate a loading dose in the clinical setting (see Phar-macokinetic Calculation section, Equation 4).8Pharmacology.indb 810/20/16 10:03 AM

Chapter 1lPharmacokineticsRedistributionIn addition to crossing the blood–brain barrier (BBB), lipid-soluble drugs redistribute into fat tissues prior to elimination.In the case of CNS drugs, the duration of action of an initial dose may dependmore on the redistribution rate than on the half-life. With a second dose, theblood/fat ratio is less; therefore, the rate of redistribution is less and the seconddose has a longer duration of action.CNSBloodDrug (D)RapidDSlowBlood–brain barrierDFatActiveInactiveFigure I-1-7. RedistributionBIOTRANSFORMATIONThe general principle of biotransformation is the metabolic conversion of drugmolecules to more water-soluble metabolites that are more readily excreted. In many cases, metabolism of a drug results in its conversion to compounds that have little or no pharmacologic activity. In other cases, biotransformation of an active compound may lead to theformation of metabolites that also have pharmacologic actions. A few compounds (prodrugs) have no activity until they undergo meta-bolic activation. Some compounds are converted to toxic metabolites, e.g., acetaminophen.DrugInactive metabolite(s)DrugActive metabolite(s)ProdrugDrugClinical CorrelateActive MetabolitesBiotransformation of thebenzodiazepine diazepam results information of nordiazepam, a metabolitewith sedative-hypnotic activity and along duration of action.Figure I-1-8. Biotransformation of Drugs9Pharmacology.indb 910/20/16 10:03 AM

Section IlGeneral PrinciplesBiotransformation Classifi ationThere are two broad types of biotransformation, called phase I and phase II.Phase I Definition: modification of the drug molecule via oxidation, reduction,or hydrolysis.–– Microsomal metabolismCytochrome P450 isozymesClinical CorrelateGrapefruit JuiceActive components in grapefruit juiceinclude furanocoumarins capableof inhibiting the metabolism ofmany drugs, including alprazolam,midazolam, atorvastatin, andcyclosporine. Such compounds mayalso enhance oral bioavailabilitydecreasing fi st-pass metabolism andby inhibiting drug transporters in theGI tract responsible for intestinal effluof drugs.ºº These are major enzyme systems involved in phase I reactions. Localized in the smooth endoplastic reticulum (microsomal fraction) ofcells (especially liver, but including GI tract, lungs, and kidney).ºº P450s have an absolute requirement for molecular oxygen andNADPH.ºº Oxidations include hydroxylations and dealkylations.ºº Multiple CYP families differing by amino acid (AA) composition, by substrate specificity, and by sensitivity to inhibitors and toinducing agents.Table I-1-2. Cytochrome P450 onesNo2C9PhenytoinWarfarinGeneral inducers*—Yes2D6Many cardiovascularand CNS drugsNone knownHaloperidolYes60% of drugs in PDRGeneral inducers*3A4MacrolidesQuinidineGeneral inhibitors†Grapefruit juiceNo* General inducers: anticonvulsants (barbiturates, phenytoin, carbamazepine), antibiotics (rifampin), chronic alcohol,St. John’s Wort.† General inhibitors: antiulcer medications (cimetidine, omeprazole), antimicrobials (chloramphenicol, macrolides, ritonavir,ketoconazole), acute alcohol.10Pharmacology.indb 1010/20/16 10:03 AM

Chapter 1lPharmacokinetics–– Nonmicrosomal metabolismHydrolysis hase I reaction involving addition of a water molecule with subseºº Pquent bond breakageºº Includes esterases and amidasesºº Genetic polymorphism exists with pseudocholinesterasesºº Example: local anesthetics and succinylcholineMonoamine oxidases etabolism of endogenous amine neurotransmitters (dopamine,ºº Mnorepinephrine, and serotonin)ºº Metabolism of exogenous compounds (tyramine)Alcohol metabolism lcohols are metabolized to aldehydes and then to acids by dehyºº Adrogenases (see CNS Pharmacology, section IV)ºº Genetic polymorphisms existPhase II Definition: Conjugation with endogenous compounds via the activity oftransferases May follow phase I or occur directly Types of conjugation:Glucuronidation–– Inducible–– M ay undergo enterohepatic cycling (Drug: Glucuronide intestinalbacterial glucuronidases free drug)–– Reduced activity in neonates, chloramphenicol and gray baby syndrome–– Morphine is activatedAcetylation–– Genotypic variations (fast and slow metabolizers)–– D rug-induced SLE by slow acetylators with hydralazine procainamide isoniazid (INH)Glutathione (GSH) conjugation–– D epletion of GSH in the liver is associated with acetaminophenhepatotoxicity11Pharmacology.indb 1110/20/16 10:03 AM

Section IlGeneral PrinciplesClinical CorrelateELIMINATIONThe elimination of a drug from thebody does not always end thetherapeutic effect. Irreversibleinhibitors, e.g. aspirin, PPIs, MAOIs,will have a therapeutic effect longafter the drug is eliminated.Concerns the processes involved in the elimination of drugs from the body (and/or plasma) and their kinetic characteristics. The major modes of drug elimination are: Biotransformation to inactive metabolites Excretion via the kidney Excretion via other modes, including the bile duct, lungs, and sweat Definition: Time to eliminate 50% of a given amount (or to decrease plasmalevel to 50% of a former level) is called the elimination half-life (t1/2).Zero-Order Elimination Rate A constant amount of drug is eliminated per unit time; for example, if 80mg is administered and 10 mg is eliminated every 4 h, the time course ofdrug elimination is:4h80 mg 70 mg4h 60 mg4h 4h 40 mg50 mg Rate of elimination is independent of plasma concentration (or amountin the body). Drugs with zero-order elimination have no fixed half-life (t1/2 is a variable). Drugs with zero-order elimination include ethanol (except low bloodUnits of drugLog units of druglevels), phenytoin (high therapeutic doses), and salicylates (toxic doses).TimeTimeFigure I-1-9a. Plots of Zero-Order KineticsFirst-Order Elimination Rate A constant fraction of the drug is eliminated per unit time (t1/2 is a con-stant). Graphically, first-order elimination follows an exponential decayversus time. For example, if 80 mg of a drug is administered and its elimination half-life 4 h, the time course of its elimination is:4h80 mg 4h40 mg 4h20 mg 4h10 mg 5 mg12Pharmacology.indb 1210/20/16 10:03 AM

Chapter 1lPharmacokinetics Rate of elimination is directly proportional to plasma level (or theamount present)—the higher the amount, the more rapid the elimination. Most drugs follow first-order elimination rates. t1/2 is a constantNoteElimination KineticsUnits of drugLog units of drug M ost drugs follow fi st order—ratefalls as plasma level falls. Z ero order is due to saturation ofelimination mechanisms; e.g., drugmetabolizing reactions have reachedVmax.Time Z ero order elimination rate isconstant; t1/2 is a variable.Time F irst order elimination rate isvariable; t1/2 is a constant.Figure I-1-9b. Plots of First-Order KineticsGraphic AnalysisPlasma levels (µg/ml)Example of a graphic analysis of t1/2:108 C06C0 plasma concentration at zero time421t 1/2123Time (h)456Figure I-1-10. Plasma Decay Curve—First-Order EliminationFigure I-1-10 shows a plasma decay curve of a drug with fi st-order eliminationplotted on semilog graph paper. The elimination half-life (t1/2) and the theoretical plasma concentration at zero time (C0) can be estimated from the graphic relationship between plasma concentrations and time. C0 is estimated by extrapolation of the linear plasma decay curve to intercept with the vertical axis. 13Pharmacology.indb 1310/20/16 10:03 AM

Section IlGeneral PrinciplesBridge to Renal PhysiologyRenal EliminationInulin clearance is used to estimateGFR because it is not reabsorbed orsecreted. A normal GFR is close to120 mL/min.The rate of elimination is the glomerular filtration rate (GFR) active secretion– reabsorption (active or passive). Filtration is a nonsaturable linear function. Ionized and nonionizedforms of drugs are filtered, but protein-bound drug molecules are not. Clearance (Cl) is the volume of blood cleared of drug per unit of time–– Cl is constant in first-order kinetics–– C l GFR when there is no reabsorption or secretion and no plasmaprotein binding–– Protein-bound drug is not cleared; Cl free fraction GFRSTEADY STATESteady state is reached either when rate in rate out or when values associatedwith a dosing interval are the same as those in the succeeding interval.Plateau PrincipleNotessMaintenance C Cl τdoseBioavailabilityThe time to reach steady state is dependent only on the elimination half-life of adrug and is independent of dose size and frequency of administration, assumingthe drug is eliminated by fi st-order kinetics.Figure I-1-11 shows plasma levels (solid lines) achieved following the IV bolusadministration of 100 units of a drug at intervals equivalent to every half-lifet1/2 4 h (τ). With such intermittent dosing, plasma levels oscillate through peaksand troughs, with averages shown in the diagram by the dashed line.Classic CluesTime and Steady State50% 1 half-life90% 3.3 half-life95% 4–5 half-life“100”% 7 half-lifePlasma Drug Cmax (peak)t 1/2t 1/2t 1/2τ50/15075/175t 1/2t 1/2t 1/288/188 94/194 97/197ssCavssCmin (trough)100/20099/199τ481216Time (h)202430Figure I-1-11. Oscillations in Plasma Levels followingIV Bolus Administration at Intervals Equal to Drug Half-LifeNote: Although it takes 7 t1/2 to reach mathematical steady state, by conventionclinical steady state is accepted to be reached at 4–5 t1/2.14Pharmacology.indb 1410/20/16 10:03 AM

Chapter 1lPharmacokineticsRate of InfusionThe figu e below shows the increase in plasma level of the same drug infused at 5different rates. Regardless of the rate of infusion, it takes the same amount of timeto reach steady state.All have the same time to plateauConcentration5 mg/min4 mg/min3 mg/minNote ose and plasma concentration (CSS)Dare directly proportional.2 mg/min1 mg/minTimeFigure I-1-12. Effect of Rate of Infusion on Plasma LevelRate of infusion (k0) does determine plasma level at steady state. If the rate ofinfusion is doubled, then the plasma level of the drug at steady state is doubled.A similar relationship can exist for other forms of drug administration (e.g., peroral)—doubling oral doses can double the average plasma levels of a drug. Plotting dose against plasma concentration yields a straight line (linear kinetics).Effect of Loading DoseIt takes 4–5 half-lives to achieve steady state. In some situations, it may be necessary to give a higher dose (loading dose) to more rapidly achieve effective bloodlevels (Cp).NoteLoading Vd Cpdose f15Pharmacology.indb 1510/20/16 10:03 AM

lGeneral PrinciplesPlasma levelSection I0Minimumlevel0TimeDosesClinical CorrelateThe loading dose equation can be usedto calculate the amount of drug in thebody at any time by knowing the Vd andthe plasma concentration.Figure I-1-13. Effect of a Loading Dose on the Time Requiredto Achieve the Minimal Effective Plasma Concentration Such loading doses are often one time only and (as shown in Figure I-1-13) are estimated to put into the body the amount of drug that should bethere at a steady state. For the exam, if doses are to be administered at each half-life of the drugand the minimum effective concentration is equivalent to CSSmin, thenthe loading dose is twice the amount of the dose used for maintenance(assuming normal clearance and same bioavailability for maintenancedoses). For any other interval of dosing, Equation 4 (below) is used.IMPORTANT PHARMACOKINETICS CALCULATIONSThe following 5 relationships are important for calculations:LegendC0 conc. at time zeroCl clearanceCp conc. in plasmaCss steady state conc.Single-Dose EquationsDC0 Volume of distribution ( Vd )Vd Half-life (t1/2 )t1/2 0.7 VdClD dosef bioavailabilityk0 infusion rateMultiple Dose (Infusion Rate) Equations Infusion rate (k0 )LD loading doseMD maintenance dose Loading dose (LD)τ dosing intervalVd volume of distribution Maintenance dose (MD)k0 Cl CssLD MD Vd Cpf Cl CSS τf16Pharmacology.indb 1610/20/16 10:03 AM

Chapter 1lPharmacokineticsChapter Summary The pharmacokinetic characteristics of a drug are dependent upon theprocesses of absorption, distribution, metabolism, and excretion. Animportant element concerning drug biodistribution is permeation, which isthe ability to cross membranes, cellular and otherwise. A drug’s ability to permeate is dependent on its solubility, the concentrationgradient, and the available surface area, which is influenced by the degreeof vascularity. Ionization affects permeation because unionized molec

USMLE is a joint program of the Federation of State Medical Boards (FSMB) and the National Board of Medical Examiners (NBME), neither of which sponsors or endorses this product. This publication is designed to provide accura

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IELTS Listening Task Type 2(Matching) (2) – teacher’s notes Description This is an activity to introduce and practise the matching task and predict some of the language students will hear. Time required: 40 minutes . Additional materials required: There is no audio for this activity – you may wish to record the dialogue on page 7 with a colleague, to use in class (or ask a student to .

1 DEATH LOOKS DOWN There was blood on the Council dais, blood on the steps, blood on the walls and the floor and the shattered remnants of the Mortal Sword. Later Emma would remember it as a sort of red mist.

Hydraulique Semestre 6 - 2009 F.L. Nom, prénom : Groupe TP : Note : /20 Canal hydraulique Durée : 3 heures 00 Contexte : Vous venez de voir en cours des notions ayant trait aux écoulements à surface libre. La visualisation des divers types d’écoulement vous permettra de faire le parallèle entre la théorie et l’expérimentation.

Texas Department of Criminal Justice FY 2021-2025 Agency Strategic Plan Agency Goals and Action Plan Page 3 GOAL 1: Probation Supervision and Community Diversions to Incarceration To provide diversions to traditional incarceration through the use of effective community supervision and other community-based programs. Action Steps to Achieve Goal a.