Principles of Pharmacology

© Sofi manning/Shutterstock 7/23/15 9:02 PM7/23/15 9:02 PM 25 Change in doses erent of that of knowledge Use of cir- © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett OR DISTRIBUTION NOT FOR SALE Generic family the of name for Altered drug eff ect occurs that Altered drug eff Drug reversibly or ligand binds that Altered drug eff ect occurs when that Altered drug eff Altered drug eff ect occurs when that Altered drug eff Process by which a drug becomes to available of solid drugs Disintegration (tablets) small into uids and body tissues. © Jones & Bartlett Learning, LLC © Jones & Bartlett OR DISTRIBUTION NOT FOR SALE © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION a drug. eliminate to Measure ability body’s of the the responsethe a drug to caused by diff drug. Dose–response curves determine doses help safe drugs. for to receptors at the same receptor site that agonistsuse that same receptor site the receptors at to initiate (active without activating receptor to site) the a reaction. certain same time or in close the herbs taken are at time. administration a drug’s to proximity particles gastrointestinal they tract in the so can that a liquid. dissolve into body fl enzymes responsible are most for drug that metabolism reactions. exchange of drugs betweenexchange systemic the circulation nervous central in the circulation system.and the cadian rhythms to time administration of drugs time administration to cadian for rhythms t and minimal harm. maximum benefi another drug is administered at the same time or in close drug the another is administered at time. administration original the to drug’s proximity when certain foods same time the taken or liquids are at time. administration a drug’s to or in close proximity 2 of Pharmacology Principles Corbett, Owens, Webb Williford Robin Laura L. King Tekoa Drug–nutrient interaction Clearance antagonist Competitive (CYP450) P-450 Cytochrome Dissolution Distribution Dose–response (dose–response relationship curve) Drug–drug interaction Drug–herb interactions Chronobiology (chronopharmacology) © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC & Bartlett Learning, © Jones SALE OR DISTRIBUTION NOT FOR LLC © Jones & Bartlett Learning, NOT FOR SALE OR DISTRIBUTION erent erent c position on erent versions of erent erent alleles. erent © Jones & Bartlett Learning, LLC. NOT FOR SALE OR DISTRIBUTION. © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett OR DISTRIBUTION NOT FOR SALE Characteristics capillaries of the sur- has Drug agonist properties that one for Chemical changes a substance undergoes falls bioavailability in which a product’s State is of an administered drug that Percentage c chromosome. Each individual inherits two prevents Drug that a receptor from being acti- of drugMovement particles gastro- from the extent the greater the attraction, the e greater Degree between of attraction a drug and a recep- activates Drug when bound a receptor that that to Chapter Glossary forms of a gene or One of a number of alternative

in the body. in the vated receptor. when bound that to intestinal tract to the systemic circulation by passive systemic the tract circulation to intestinal absorption, active transport, or pinocytosis. tor. Th tor. of binding. rounding the brain that create a natural barrier to the barrier a natural the to create brain that the rounding within 80% to 125% of the bioavailability of the refer- of the bioavailability 125% of the within 80% to drug.ence If two products bioequivalent, are can one usually be other. substituted the for DNA sequence that is locatedDNA sequence a specifi that at a specifi same, the the each two alleles are alleles for gene. If the person is homozygous. If they diff are person gene, the the is heterozygous. Genes can have forms or diff erent several diff tissues. target the to available receptor. opioid receptor and antagonist propertiesopioid receptor and antagonist a diff for type of opioid receptor. © Jones & Bartlett Learning, LLC © Jones & Bartlett OR DISTRIBUTION NOT FOR SALE © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION

Biotransformation Blood–brain barrier Antagonist Bioavailability Bioequivalence Agonist Agonist–antagonist Allele Absorption Affinity ✜ 9781284078879_CH02.indd 259781284078879_CH02.indd 25 © Jones & Bartlett Learning, LLC & Bartlett Learning, © Jones SALE OR DISTRIBUTION NOT FOR © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, NOT FOR SALE OR DISTRIBUTION 26 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOREfficacy SALE Capacity OR toDISTRIBUTION induce a therapeutic response. As NOTMinimum FOR effective SALE concentration OR DISTRIBUTION Minimum concentration of a opposed to eff ectiveness, which is the ability of a drug to drug in serum required to produce a desired pharma- produce a therapeutic response in real life conditions. cologic eff ect. Elimination Removal of a drug or its metabolites whereby Narrow therapeutic index As defi ned by the Food and Drug the drug or metabolites are changed to a water-soluble Administration, less than a twofold diff erence between form, and thereby removed© Jones via the & kidneys;Bartlett less Learning, com- LLCthe median eff ective dose and© the Jones median & lethal Bartlett dose. Learning, LLC mon elimination routesNOT include FOR liver, SALE bile, feces, OR saliva,DISTRIBUTION Noncompetitive antagonist Drug or ligandNOT thatFOR reversibly SALE binds OR DISTRIBUTION lungs, sweat, and breast milk. to a receptor at a site diff erent from the active site used Enteric coating Drug coating applied to slow the release and by agonists; this binding causes a structural change that absorption of a drug in the stomach. inhibits the agonist from binding to the active site. Non- Excretion © Elimination Jones & of Bartlett a drug from Learning, the biologic LLC system. competitive© antagonists Jones & do Bartlett not compete Learning, for the active LLC Extended NOTrelease (sustainedFOR SALE release, OR slow DISTRIBUTIONrelease) Drug designed binding siteNOT but they FOR do have SALE an antagonist OR DISTRIBUTION eff ect. to be released over an extended period of time. Partial agonist Drug molecule that elicits a partial pharma- First-pass metabolism (first-pass effect) Drug metabolism that cologic response. occurs as a drug passes through the intestinal lumen, Peak level Highest plasma drug concentration. portal vein, and liver prior to entering the systemic cir- P-glycoprotein Permeability glycoprotein (P-gp); a trans- © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC culation. Also known as hepatic fi rst pass. membrane protein that serves as a drug transporter NOT FORG-protein–coupled SALE OR receptor DISTRIBUTION Type of cell membrane receptor. NOTand FOR moves SALE drugs OR out DISTRIBUTIONof cells. Also known as multidrug Th e drug binds with this receptor, which then binds resistance protein 1 (MDR1) or ATP-binding cassette with guanosine triphosphate (GTP) and activates an subfamily B member 1 (ABCB1). eff ector (enzyme) in the cell. Pharmacodynamics Study of drug concentration and the Half-life Time it takes for ©half Jones of the drug & Bartlett concentration Learning, to LLCrecipient’s response; the study© of Jones a drug’s eff& ects,Bartlett includ- Learning, LLC be eliminated from theNOT body (FORt½). SALE OR DISTRIBUTIONing the duration and the magnitudeNOT FOR of the SALE response OR in DISTRIBUTION Hydrophilic Drug that is water soluble. A drug or drug relationship to the drug dose. metabolite must be hydrophilic to be excreted in urine. Pharmacokinetics Process of drug absorption, distribution, Inducer Drug that stimulates production of one of the metabolism, and elimination. CYP450© Jones enzymes, & which Bartlett in turn Learning, rapidly metabolizes LLC the Phase I reaction ©First Jones half of & enzymatic Bartlett metabolism,Learning, which LLC substrate drug. Th is can results in a decreased thera- makes a drug water soluble so it can be excreted; it includes NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION peutic eff ect of the substrate drug. oxidation, hydrolysis, and/or reduction reactions. Inhibitor Drug that prevents production of a CYP450 Phase II conjugation reaction Second half of the drug metabo- enzyme, which in turn decreases metabolism of the lism process, which makes the drug polar and fi nalizes substrate drug. Th is results in an increased plasma level the changes that make it water soluble. © Jones &of theBartlett substrate Learning, drug and, therefore, LLC an increased thera- © JonesPolymorphism & Bartlett One of two Learning, or more naturally LLC occurring vari- NOT FORpeutic SALE eff ect,OR adverse DISTRIBUTION drug reaction, and/or toxic eff ect. NOTants FOR of aSALE particular OR DNA DISTRIBUTION sequence on a chromosomal Inverse agonist Drug that binds to receptors that have an locus. Th e DNA variant is termed a polymorphism (as intrinsic or basal activity, which results in antagonism opposed to a mutation) when it appears in more than of this basal activity and downregulation of the recep- 1% of a population. Two types of polymorphisms are tor’s eff ect. Antihistamines are inverse agonists. distinguished: insertions/deletions and single-nucleo- © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Ligand Drug or chemical that binds to a specifi c receptor. tide polymorphisms (SNP) wherein there is a change in Lipophilic Drug that has aNOT high affiFOR nity SALE for fat. ORLipophilic DISTRIBUTION the order of an amino acid base.NOT FOR SALE OR DISTRIBUTION drugs transfer readily across the phospholipid cell Polypharmacy Concurrent use of many diff erent drugs and/ membrane. or excessive use in excess of that which is clinically Loading dose Administration of a large initial drug dose. recommended. Maximum© effect Jones Maximum & Bartlett drug eff Learning,ect; it varies by LLC drug. Potency Concentration© Jones at &which Bartlett a drug Learning, elicits 50% ofLLC its MetabolismNOT Change FOR of SALE a drug, OR primarily DISTRIBUTION in the liver by maximal response.NOT FOR SALE OR DISTRIBUTION CYP450 enzymes, into metabolites that may be phar- Prodrug Biologically inactive or partially active drug that macologically active or inactive. Drug metabolism alters is changed as a result of the body’s metabolism into an a drug so that it may be eliminated. active drug. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 26 7/23/15 9:02 PM The Nature of Drugs 27 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALEProtein bindingOR DISTRIBUTION Fraction of total drug in the plasma thatNOT is FOR SALE OR DISTRIBUTION bound to plasma proteins. ❚ Introduction Receptor Protein or molecular complex that, when bound to a ligand (drug), either initiates a physiologic response During a typical lifespan, the average woman will take or blocks the specifi c response that the receptor numerous medications, including prescription and non- normally stimulates.© Jones & Bartlett Learning, LLCprescription agents, and perhaps© Jones some & naturalBartlett medicinal Learning, LLC Steady state When drugNOT elimination FOR SALE equals OR drug DISTRIBUTION availabil- substances such as herbsNOT or other FOR dietary SALE supplements. OR DISTRIBUTION ity. Average concentration of the drug remains constant Th ese chemicals, via their action on physiologic processes, when it reaches a steady state. can be used to produce therapeutic benefi t but can also Therapeutic effect Desired physiological or psychological cause toxic eff ects. Th is chapter reviews basic pharmacologic principles as applied to women’s health. ©response Jones to & a drug.Bartlett Learning, LLC © Jones & Bartlett Learning, LLC TherapeuticNOT FOR equivalence SALE State OR in DISTRIBUTION which two diff erent drugs NOT FOR SALE OR DISTRIBUTION are pharmaceutically equivalent (contain the same active ingredient at the same dose) and have the same ❚ The Nature of Drugs clinical eff ect with regard to both safety and effi - cacy when administered under specifi ed conditions. Before a drug can elicit a physiologic response, it must © Jones & BartlettTh e FDA Learning, has criteria LLC for determining therapeutic© Jones be absorbed& Bartlett into Learning,the body and LLC transported from a site of NOT FOR SALEequivalence. OR DISTRIBUTION NOT FORadministration SALE OR to the DISTRIBUTION site of action. In most cases, the chem- Therapeutic index Guideline that estimates the margin of ical (or drug) interacts with a specifi c target or receptor safety of a drug through the use of a ratio that measures in the biologic system. Th ere are several diff erent types of the eff ective dose in 50% of the population and the lethal receptors in the body. Many of them are located on the cell dose in 50% of the© population.Jones & Bartlett Learning, LLCmembrane (Figure 2-1). For© aJones drug to possess& Bartlett the ability Learning, to LLC Therapeutic range (therapeuticNOT FOR window) SALE Plasma OR drug DISTRIBUTION concen- produce medical benefi ts, NOTit must FOR have the SALE appropriate OR DISTRIBUTION size, tration between the minimum eff ective concentration electrical charge, shape, and composition to interact with a in the plasma for obtaining the desired drug action and receptor and produce an eff ect. Interestingly, most receptors the mean toxic concentration. in the body exist naturally as targets for endogenous chemi- Volume of distribution Relationship between the dose of the cals such as epinephrine, serotonin, or estrogen. Th us, drugs ©drug Jones administered & Bartlett and theLearning, serum concentration LLC after used for pharmacologic© Jones & purposesBartlett often Learning, have some LLC structural NOTadministration. FOR SALE OR DISTRIBUTION similarityNOT to chemicals FOR SALE made naturally OR DISTRIBUTION within the body. In Xenobiotic Chemical found in an organism that is not nor- addition, the drug should be able to leave the biologic system mally produced or expected to be present. Drugs can through elimination or inactivation in a reasonable amount be xenobiotics, but the term is more frequently used to of time so that the drug’s actions are not inappropriately © Jones & Bartlettrefer to Learning,toxins and poisons. LLC © Joneslong & or Bartlett permanent. Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Receptor

Extracellular (outside the cell) Water Soluble Layer © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Fat Soluble Layer © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Intracellular (inside the cell) Figure 2-1 Cell membrane receptor.

9781284078879_CH02.indd 27 7/23/15 9:02 PM 28 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION Administered dose is madeNOT FORAffected SALE by OR DISTRIBUTION Pharmacologic available for absorption into • Medication errors phase circulatory system • Factors affecting individual use

© Jones & Bartlett Learning, LLC Affected by © Jones & Bartlett Learning, LLC Absorption (gut → plasma) • Drug characteristics PharmacokineticNOT FOR SALEDistribution OR (plasma DISTRIBUTION → tissue) • Variables within the GI tractNOT FOR SALE OR DISTRIBUTION phase Metabolism (liver, lung) • Individual genetic variables Excretion (kidney) • Disorders that alter pharmacokinetics • Drug interactions

© Jones & Bartlett Learning, LLC Affected© by Jones & Bartlett Learning, LLC Drug-receptor interactions Pharmacodynamic • Individual genetic variables NOT FOR SALE OR DISTRIBUTIONTherapeutic effects NOT FOR SALE OR DISTRIBUTION phase • Disorders that alter Adverse effects pharmacokinetics • Drug interactions Figure 2-2 Factors that determine the intensity of drug responses. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Drugs can be solid, liquid, or gaseous at room known pharmacokinetic principles of drug absorption, temperature. Th is physical nature of the chemical often distribution, metabolism, and excretion but is based on determines the best route© through Jones which & Bartlett the drug Learning,should the LLC woman’s disease state and© takes Jones into &consideration Bartlett Learning, LLC be administered. ExamplesNOT of FORroutes SALEof administration OR DISTRIBUTION individual-specifi c factors. A commonNOT FOR example SALE is when OR a DISTRIBUTION include intravenous (IV), intramuscular (IM), subcutane- laboratory measures a person’s serum or plasma drug level. ous (SQ), inhalation, and transdermal (TTS), as well as Th is numerical value is combined with knowledge of the enteral administration, such as oral (PO), rectal (PR), and disease state and conditions that infl uence the distribu- sublingual (SL). Routes of administration vary depending tion of that particular drug. Kinetic principles can then on the physiochemical© Jones & Bartlett properties Learning, of the drug, LLC including be applied and© used Jones to modify & Bartlett the drug Learning, dose and subse- LLC its molecularNOT weight, FOR SALEfat or water OR solubility, DISTRIBUTION and degree of quent drug serumNOT levels FOR to SALEproduce OR desirable DISTRIBUTION changes in ionization. Additionally, the route of administration aff ects the individual’s disease state. Examples of drugs for which the speed of absorption. Diff erent routes may require vari- serum plasma levels are drawn for clinical decision making ous doses and dosage forms. include magnesium sulfate, vancomycin (Vanocin), the- © Jones &In Bartlettconsidering Learning, all of the aforementioned LLC factors, it is © Jonesophylline & (Th Bartlett eo-Dur), Learning, phenobarbital LLC (Luminal), lithium NOT FORdiffi cultSALE to conceptualize OR DISTRIBUTION how safe and eff ective drugs are NOT(Lithobid), FOR SALEand digoxin (Lanoxin). OR DISTRIBUTION developed and utilized for benefi cial eff ects in the human body. Th e multitude of changes a drug undergoes between its Absorption administration and its stimulation of the intended response After a drug is administered, it should be able to reach are divided into two major categories. Pharmacokinetics its intended site of action. Th is requires that the drug be refers to the changes that© Jonesa drug undergoes & Bartlett during Learning, its LLC © Jones & Bartlett Learning, LLC absorbed into the circulation from its site of adminis- course through the body.NOT Pharmacodynamics FOR SALE OR refers DISTRIBUTION to NOT FOR SALE OR DISTRIBUTION tration (Table 2-1).1 Drugs can be absorbed via passive the physiologic eff ects that the drug has on body function diff usion, active diff usion, or pinocytosis. Most drugs (Figure 2-2). rely on passive diff usion. When a drug has a structure similar to a physiologic compound that moves across © Jones & Bartlett Learning, LLC cell membranes© Jonesvia active & Bartletttransport, Learning,it is likely to LLC be ❚ PharmacokineticsNOT FOR SALE OR DISTRIBUTION transported viaNOT active FOR transport SALE as OR well. DISTRIBUTION Penicillin, for example, moves into the circulatory system via active Pharmacokinetics specifi cally focuses on the kinetics transport. Macromolecules such as insulin and drugs of drug absorption, distribution, metabolism, and made of large proteins access the circulatory system via © Jonesexcretion & Bartlett. Clinical Learning, pharmacokinetics LLC incorporates © pinocytosis.Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 28 7/23/15 9:02 PM Pharmacokinetics 29 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALETable 2-1 OR Absorption DISTRIBUTION Speed of Various Drug Formulations NOT FORcompartment SALE OReasily. DISTRIBUTION Th e pH in the gastrointestinal tract also aff ects this process because the proportion of a drug that Type of Formulation Absorption Rate is un-ionized or lipophilic depends on the pH of the envi- Oral Formulations ronment. Th e stomach is acidic with a low pH, and drugs Liquids, syrups, and elixirs Fastest that are weak acids are mostly in their un-ionized form in Suspensions © Jones & Bartlett Learning, LLCan acidic environment. Th erefore,© Jones weak & acids Bartlett such as aspirinLearning, LLC Powders NOT FOR SALE OR DISTRIBUTIONwill readily be absorbed inNOT the stomach. FOR SALEConversely, OR the DISTRIBUTION pH Capsules Tablets in the small intestine is more basic, and weak bases are more Coated tablets likely to be in their un-ionized form in this environment. Enteric-coated tablets Slowest Parenteral© Jones Formulations & Bartlett Learning, LLC Oral Administration© Jones & Bartlett Learning, LLC IntravenousNOT FOR (IV) SALE OR DISTRIBUTIONFastest AdministeringNOT drugsFOR orally SALE is the OR preferred DISTRIBUTION route of admin- Intramuscular (IM) istration because it is safe, inexpensive, and convenient Subcutaneous (SC) compared to other routes. Orally administered drugs Intrathecal (IT) (typically in tablet or capsule forms) must disintegrate Epidural Slowest © Jones & Bartlett Learning, LLC © Jonesinto & smaller Bartlett particles, Learning, dissolve inLLC the gastric fl uid, and pass Source: Data from Guittierrez K. Pharmacotherapeutics. 2nd ed. St. Louis: across the cell membranes within the gastrointestinal (GI) NOT FOR SALESaunders OR Elsevier; DISTRIBUTION 2008: 44.1 NOT FOR SALE OR DISTRIBUTION tract to be absorbed into the circulation. In addition, pas- Role of pH sage through the GI tract must alter the chemical characteristics of drugs that rely on passive diff usion so they Most drugs are weak organic acids or bases that exist in become un-ionized and lipid soluble. either an ionized or© un-ionized Jones & form. Bartlett Acidic Learning,drugs are in LLC The oral route of administration© Jones &does Bartlett possess Learning, some LLC an un-ionized formNOT that is FOR lipid solubleSALE or OR lipophilic DISTRIBUTION; as a disadvantages (Figure 2-3).NOT Some FOR drugs SALE have OR limited DISTRIBUTION consequence, they diff use easily across the phospholipid absorption secondary to how their chemical charac- bilayer cell membrane. Basic drugs are in an ionized form teristics respond to the environment of the GI tract, and are water soluble or hydrophilic. Th ese drugs can- including the low pH of gastric acid, destruction by gas- not© pass Jones through & Bartlett the cell membrane Learning, into LLCthe intracellular tric enzymes,© Jones differences & Bartlett in gastric Learning, emptying LLCrates, and NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Drug characteristics: Drug compositiona

Stomach: pH in stomachb and © Jones & Bartlett Learning, LLC © Jones & Bartlettintestine, presenceLearning, of food LLC in NOT FOR SALE OR DISTRIBUTIONDuodenum StomachNOT FOR SALEstomach OR or intestineDISTRIBUTIONc

Gastric emptying time Upper small intestine

Gut motility and surface © Jones & Bartlett Learning, LLC area in small intestine©d Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONLower small intestine NOT FOR SALE OR DISTRIBUTION Blood flow to the small intestine

aVarious aspects of the drug’s chemical characteristics will affect absorption. For example, enteric coating will slow absorption, and drugs that are lipid-soluble will be absorbed more rapidly. © Jones & BartlettbPresence Learning, of antacid in the LLC stomach will change the pH. This increases© Jones absorption & of Bartlett basic drugs Learning, LLC NOT FOR SALEand OR decreases DISTRIBUTION absorption of acidic drugs. NOT FOR SALE OR DISTRIBUTION cFood that is in the stomach or intestine can either facilitate or interfere with drug absorption. dThe small intestine has the greatest surface area, which is why most drugs are absorbed in the small intestine. Figure 2-3 Factors that aﬀ ect absorption of drugs. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 29 7/23/15 9:02 PM 30 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC 3 NOT FORadverse SALE drug OR reactions DISTRIBUTION such as vomiting due to gastric NOTdrug. FOR Th ese SALE formulations OR DISTRIBUTION should not be crushed, chewed, irritation. Infants and older individuals have less gastric or scored (broken). acidity, which, in general, decreases drug absorption. The effect of food that is present in the GI tract also First-Pass Metabolism influences the absorption of drugs, albeit in a very drug- After an orally administered drug enters the body, it passes specific manner.1 Some ©drugs Jones are best & Bartlett taken with Learning, food LLC © Jones & Bartlett Learning, LLC to minimize gastrointestinalNOT irritation,FOR SALE whereas OR DISTRIBUTIONother through the intestine, intestinalNOT wall, the FOR portal SALE blood OR sys- DISTRIBUTION drugs’ absorption may be impeded by food. Also, spe- tem, and the liver before it enters the systemic circulation. cific foods may enhance drug absorption. Most drugs undergo metabolic changes during this trip via Some drugs have an enteric coating that is intended their interaction with (1) bacterial enzymes in the intes- to prevent© Jonesthe drug’s & disintegration Bartlett Learning, and absorption LLC in the tine; (2) permeability© Jones glycoprotein, & Bartlett usually Learning, referred toLLC as P-glycoprotein (P-gp), which is a multidrug effl ux pump stomachNOT with subsequent FOR SALE absorption OR DISTRIBUTION in the less acidic small NOT FOR SALE OR DISTRIBUTION intestine. In addition, extended-release (also known as present in the brush border membrane of gastrointesti- sustained-release or slow-release) drugs may have multiple nal cells; (3) cytochrome 450 enzymes (CYP450 enzymes) compressed coatings to allow release of the drug over time. present in gastrointestinal cells; and (4) CYP450 enzymes Th ese preparations are designed to produce slow, uniform in the liver. Drug metabolism is called biotransformation © Jonesabsorption & Bartlett of the Learning, drug for 8 hours LLC or more. Th e advantages © Jonesbecause the& Bartlettstructure of Learning, the drug is altered LLC chemically. Th e NOT FORof the SALE coated OR preparations DISTRIBUTION compared to their immediate- NOTbiotransformation FOR SALE thatOR occursDISTRIBUTION before the drug enters the release counterparts include longer dosing intervals, mainte- systemic circulation is referred to as fi rst-pass metabolism nance of a therapeutic eff ect for a prolonged period of time, or the fi rst-pass eff ect.4,5 and decreased incidence and/or intensity of both undesired As a result of fi rst-pass metabolism, a proportion of the eff ects and nontherapeutic© blood Jones levels & ofBartlett the drug. Learning, Often, drug LLC dose fails to enter the systemic© Jones circulation, & Bartlett thereby Learning, LLC these drugs are designatedNOT by abbreviations FOR SALE such asOR CR DISTRIBUTION (con- reducing the drug’s bioavailabilityNOT (Figure FOR 2-4). SALE Estrogen, OR DISTRIBUTION trolled release), LA (long acting), or SR (sustained release). for instance, is extensively metabolized in the liver via the To add to this confusion, “extended release” is the term rec- fi rst-pass eff ect. Alternative routes of administration for ommended by the U.S. Pharmacopeia, but extended-release estrogen compounds such as patches and vaginal rings formulations can be labeled XL, XR, or ER depending on have been devised to decrease the amount of drug that the choice© ofJones the pharmaceutical & Bartlett company Learning, that marketsLLC the must be administered© Jones to accommodate & Bartlett the Learning, fi rst-pass eff LLC ect. NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Bile

i l NOT FOR SALE OR DISTRIBUTION e NOT FOR SALE OR DISTRIBUTION B lo Intestine o d s tre am © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Figure 2-4 Hepatic ﬁ rst-pass metabolism. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 30 7/23/15 9:02 PM Pharmacokinetics 31 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALERole of Enterohepatic OR DISTRIBUTION Circulation NOT FORDrugs SALE in aqueousOR DISTRIBUTION solution are absorbed rapidly after intramuscular injection. Th is rate can be altered if the rate Some drugs are recycled through the enterohepatic of blood fl ow surrounding the injected area is increased, circulation. When this occurs, there is an increased risk as can happen during local heating (e.g., a hot bath), mas- 6 that their toxic eff ects will be manifested. Once these sage, or exercise. All of these measures increase vasodila- drugs enter the liver© and Jones are taken & Bartlettup by hepatocytes, Learning, they LLCtation, which in turn increases© Jones drug &absorption Bartlett into Learning, the LLC are excreted into bileNOT either FOR unchanged SALE or OR as metabolites.DISTRIBUTION systemic circulation. A slow,NOT constant FOR absorption SALE OR from DISTRIBUTION the After the bile enters the gastrointestinal tract, the excreted intramuscular site can be achieved if the drug is injected in drug is reabsorbed into the hepatic circulation, which can solution in oil vehicles; indeed, antibiotics are often admin- result in another peak in the plasma concentration of the istered in this manner. drug or hepatotoxicity. © Jones & Bartlett Learning, LLC Because© Jonesintravenous & Bartlett administration Learning, injects LLCthe drug In summary, determinants of drug absorption fol- NOT FOR SALE OR DISTRIBUTION directly intoNOT the FOR systemic SALE circulation, OR DISTRIBUTION 100% bioavailability lowing oral administration include properties that aff ect is achieved. No fi rst-pass eff ect occurs, and there are no dissolution such as dosage forms, pH in the stomach and barriers (e.g., skin) to drug absorption with this route. Th e small intestine, and the size of the tablet. Th e next deter- drug delivery is controlled and achieved with an accuracy minant is gastric emptying time, which is aff ected by the and immediacy not possible by the other routes. Drugs that © Jones & Bartlettpresence of Learning, food, antacids, LLC or other drugs, as well as ©dis- Jonescannot & Bartlett be administered Learning, intravenously LLC include drugs in an NOT FOR SALEease processes OR DISTRIBUTION that might exist in the GI tract. IntestinalNOT FORoily vehicle,SALE drugsOR DISTRIBUTIONthat precipitate blood constituents or motility then aff ects the amount of time a drug is presented hemolyze erythrocytes, and drug combinations that result to the gastric lumen cells and, occasionally, the time avail- in the formation of precipitates. able for drug degradation by microfl ora in the gut. Next, chemical properties of the drug such as water versus lipid © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC solubility aff ect drug passage through the intestinal endo- Sublingual Administration NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION thelial cells, and some drugs are metabolized by the intesti- Sublingual administration occurs when a drug is placed nal endothelium or partially returned to the intestinal tract under the tongue and absorbed into the blood. For some by P-gp. Finally, the extent to which a drug is metabolized drugs, the sublingual route can be a convenient route of via the fi rst-pass eff ect will dictate the dose that must be administration that bypasses the fi rst-pass eff ect. Th e used© Jonesfor oral administration. & Bartlett Learning, LLC venous drainage© Jones from & theBartlett mouth Learning,is to the superior LLC vena NOT FOR SALE OR DISTRIBUTION cava, whichNOT protects FOR the SALE drug from OR rapid DISTRIBUTION fi rst-pass metabo- Parenteral Administration lism. Nitroglycerin is administered via sublingually because it is absorbed rapidly through this route; in contrast, if Drugs administered by parenteral routes (intravenous, sub- administered orally, it undergoes extensive metabolism by cutaneous, or intramuscular) bypass the GI tract, which the liver until it reaches the point at which it essentially is © Jones & Bartlettallows for Learning,a more rapid, LLC extensive, and predictable drug© Jones removed & Bartlett from the Learning, circulation. LLC NOT FOR SALEabsorption OR as DISTRIBUTION compared to other routes of administration.NOT FOR SALE OR DISTRIBUTION In the case of subcutaneous and intramuscular admin- Transdermal Administration istration, the drug creates a depot under the skin and is absorbed into the systemic circulation by simple diff usion. Transdermal administration refers to the administration of Th e rate of absorption© forJones these routes& Bartlett is limited Learning, by the area LLCa drug molecule through ©the Jones skin for &absorption Bartlett into Learning, the LLC of the absorbing capillaryNOT FORmembranes SALE and OR by theDISTRIBUTION solubil- circulation. Transdermal NOTpreparations FOR SALEare developed OR DISTRIBUTION to ity of the substance in the interstitial fl uid. A subcutaneous deliver a consistent drug dose over a day or a period of days. injection can be used only for drugs that are not irritating to Not all drug molecules can readily penetrate intact skin, but tissue; otherwise, severe pain, necrosis, and tissue sloughing when they are able to do so, the amount absorbed depends may occur. Th e rate of absorption following subcutaneous on the surface area over which the drug is applied and on injection© Jones of a &drug Bartlett often is Learning,suffi ciently constant LLC and slow lipid solubility© Jones (the epidermis& Bartlett behaves Learning, as a lipid LLC barrier). toNOT provide FOR a sustained SALE effOR ect. DISTRIBUTION Th is slow and constant rate TransdermalNOT administration FOR SALE can OR be DISTRIBUTION convenient for some is used and altered intentionally, as in the case of insulin: individuals, and this dosage form has become more popular Altering the particle size, protein complex, and pH can pro- in recent years. Controlled-release topical patches that have vide for short (3–6 hours), intermediate (10–18 hours), and become increasingly available include nicotine for tobacco- © Jones & Bartlettlong-acting Learning, (18–24 hours) LLC preparations of this hormone.© Jonessmoking & Bartlett withdrawal, Learning, scopolamine LLC (Transderm-Scop) for NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 31 7/23/15 9:02 PM 32 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORmotion SALE sickness, OR nitroglycerin DISTRIBUTION for angina pectoris, estrogen NOTalthough FOR it SALEhas a slower OR onset DISTRIBUTION of action. Systemic absorption (e.g., Vivelle, Climara, Estraderm) for menopausal therapy, is unlikely but does increase if the drug molecule is applied and estrogens plus progestins for contraception. Systemic to mucous membranes. Drugs given via topical administra- absorption of drugs occurs much more readily through tion include ophthalmic drugs, which may take the form of abraded, burned, or denuded skin because the dermis is drops or an ointment; erythromycin ointment (Ilotycin), freely permeable. Also, when© Jones the skin & isBartlett infl amed Learning, (caus- for LLC example, often is administered© Jonesto newborns & Bartlett in the fi rst Learning, LLC ing an increase in cutaneousNOT blood FOR fl ow), SALE drug OR molecules DISTRIBUTION few hours after birth to preventNOT ophthalmic FOR SALEneonatorum. OR DISTRIBUTION can more easily pass through the skin layer. Toxic eff ects Likewise, otic drugs (ear drops) may be given via topical can occur if highly lipid-soluble drug molecules are applied administration to treat infections or to facilitate removal of to skin that is not intact, so one must avoid transdermal cerumen. Both ophthalmic and otic drugs require diligence administration© Jones in this & Bartlettsituation. Learning,Conversely, lotionLLC and in identifying the© Jonescorrect eye/ear & Bartlett for administration, Learning, appro- LLC ointmentsNOT on the FOR skin SALEtend to impairOR DISTRIBUTION drug transfer through priate positioningNOT of theFOR individual SALE for OR drug DISTRIBUTION administration, transdermal administration. and administration techniques specifi c to the drug medium.

Rectal Administration In summary, factors that aff ect absorption are important considerations for the clinician because the drug must reach When a drug is administered rectally, the drug molecule © Jones & Bartlett Learning, LLC © Jonesits intended & Bartlettsite of action Learning, before it can LLC begin to produce a either is absorbed into the systemic circulation or placed NOT FOR SALE OR DISTRIBUTION NOTchange FOR in the SALE biologic OR system. DISTRIBUTION However, in the end, the clini- to induce a localized eff ect, as in the case of hydrocortisone cian is primarily concerned with bioavailability rather than suppositories for hemorrhoids. Th is route of administration the absorption of the drug. Bioavailability is a term used can be the preferred route when the individual is nause- to indicate the proportion of a drug dose that reaches its ated, vomiting, or unconscious. Th e potential for fi rst-pass intended site of action when administered by any route. metabolism is less than that© Jones noted with & Bartlett the oral route Learning, of LLC © Jones & Bartlett Learning, LLC administration because approximatelyNOT FOR 50% SALE of the OR drug DISTRIBUTION that Distribution NOT FOR SALE OR DISTRIBUTION is absorbed from the rectum will bypass the portal system. However, rectal absorption often is irregular and incomplete, Following a drug’s administration and subsequent absorp- and many drugs can cause irritation of the rectal mucosa. tion into the systemic circulation, the drug becomes © Jones & Bartlett Learning, LLC distributed into© interstitial Jones and& Bartlett intracellular Learning, fl uids by passive LLC mechanisms such as diff usion or by specifi c drug transport PulmonaryNOT Administration FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION mechanisms. Distribution of the drug varies depending on Some drugs are inhaled and subsequently absorbed through multiple factors, including the size of the drug molecule, the pulmonary epithelium and mucous membranes of the the drug’s affi nity for aqueous and lipid tissues, tissue per- respiratory tract. Systemic absorption of drug molecules meability, systemic circulation, protein binding, and pH. © Jonesthrough & Bartlett this route Learning, is typically rapidLLC due to the lungs’ large © JonesTh ese factors & Bartlett collectively Learning, determine the LLC rate of delivery and NOT FORsurface SALE area. ORAdvantages DISTRIBUTION of this route of administration NOTpotential FOR amount SALE of OR drug DISTRIBUTION distributed into tissues. include rapid absorption of a drug molecule into the blood, Th ere are two main phases of distribution. Th e fi rst avoidance of fi rst-pass metabolism, and local application phase occurs when most of the well-perfused organs (e.g., of the drug at the desired site of action in the case of pul- liver, kidney, and brain) receive most of the drug. During monary disease such as asthma. Inhaled drugs are often the second phase of distribution, the less well-perfused administered by nebulizer© or Jones a metered-dose & Bartlett inhaler Learning, that organs LLC receive concentrations of© the Jones drug. Th & eseBartlett less well- Learning, LLC can create aerosols of smallNOT particles. FOR SALEFor example, OR DISTRIBUTION alb- perfused organs include muscle,NOT most FOR viscera, SALE skin, ORand DISTRIBUTION uterol (Proventil HFA) may be administered by inhaler fat. Th is second distribution phase may require minutes to for individuals experiencing an acute asthma attack. More several hours before the concentration of the drug in tissue than one treatment may be required, depending on the is in equilibrium with the concentration in the circulation. severity© of Jonesthe attack & and Bartlett the person’s Learning, response toLLC the drug. Several clinically© Jones important & Bartlett pharmacokinetic Learning, processes LLC NOT FOR SALE OR DISTRIBUTION occur as a drugNOT is distributed. FOR SALE OR DISTRIBUTION Topical Administration Steady State When the drug is intended for local action (e.g., administration of eye drops for glaucoma), it is administered Steady state refers to the concentration of a drug in the © Jonestopically. & Bartlett Drug absorption Learning, through LLC this route is continuous, © Jonessystemic &circulation Bartlett thatLearning, will eventually LLC be achieved NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 32 7/23/15 9:02 PM Pharmacokinetics 33 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Peak NOT FORSteady SALE state is ORusually DISTRIBUTION reached after 4 to 5 half-lives. Complete NOT FOR SALE OR DISTRIBUTIONTrough Steady State elimination also takes approximately 4 to 5 half lives once the 97% drug is no longer administered; (Figure 2-6). 94% 88% Another important concept when considering drug 75% administration is loading dose. A loading dose is one or © Jones & Bartlett Learning, LLCa series of doses that may© be Jones given at &the Bartlett onset of therapy Learning, LLC 50% NOT FOR SALE OR DISTRIBUTIONwith the aim of achievingNOT the targetFOR plasmaSALE concentra-OR DISTRIBUTION

Concentration of drug tion rapidly. Th is dose, or series of doses, is used to rapidly attain a steady state when the treatment of the individual 1234 5 necessitates a quick therapeutic response. © Jones & BartlettHalf Learning, lives LLC Volume© Jonesof distribution & Bartlett refers Learning, to the apparent LLC volume (V ) in which the drug is dissolved. In other words, FigureNOT 2-5 FOR Steady stateSALE after OR repeated DISTRIBUTION drug dosing. DNOT FOR SALE OR DISTRIBUTION VD relates to the concentration of drug in plasma and the amount of drug in the body. Th e volume of distribution does not have a true physiologic meaning in terms of when the rate of drug elimination equals the rate of drug an anatomic space. However, it often is used to calculate © Jones & Bartlettavailability. Learning,7 Th is concept LLC is often used in calculations© ofJones the &loading Bartlett dose Learning,of a drug that LLC will immediately achieve a NOT FOR SALEdrug dose OR and DISTRIBUTION interval between doses (Figure 2-5). NOT FORdesired SALE steady-state OR DISTRIBUTION drug level because it refers to the relationship between the dose of the drug administered and Half-Life the serum concentration after administration. Half-life refers to the time it takes for the plasma concentration Plasma Protein Binding or the amount of drug© Jones in the body & Bartlett to be reduced Learning, by 50% LLC © Jones & Bartlett Learning, LLC or one half. Half-lifeNOT is important FOR becauseSALE itOR determines DISTRIBUTION the Protein binding is perhapsNOT the FOR most SALEimportant OR factorDISTRIBUTION time required to reach steady state and the dosage interval. when a drug is in the systemic circulation. Plasma protein

5 mg Plasma concentration © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR2.5 mgSALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

1.25 mg 0.625 mg © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC X3 h6 h 9 h 12 h 15 h NOT FOR SALE OR DISTRIBUTION Time (hours) NOT FOR SALE OR DISTRIBUTION

Half-lives 1 2 3 4 5 Figure 2-6 Elimination half-life determination. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 33 7/23/15 9:02 PM 34 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONUnbound drug in NOTbound. FOR For SALE example, OR the DISTRIBUTIONaminoglycoside antibiotic known circulation as gentamicin (Garamycin) has a high affi nity for kidney tissue, and it can cause local toxicity to the kidney if drug levels become too high. Other examples of tissue binding include drugs that are © Jones & Bartlett Learning,lipophilic, LLC which have a high affi © nity Jones for fat &and Bartlett for bone. Learning,8 LLC NOT FOR SALE OR DISTRIBUTIONHighly lipid-soluble drugs canNOT be stored FOR in SALE fat tissues, OR DISTRIBUTION Albumin-drug complex Free drug diffusing which results in fat becoming a drug reservoir. Fat is a rela- into tissue tively stable reservoir because it has low blood fl ow. Bone is Figure 2-7 Protein binding of drugs. another tissue that is subject to tissue binding of lipophilic © Jones & Bartlett Learning, LLC drugs. Such drugs© Jones can accumulate & Bartlett in bone Learning, by adsorption LLC NOT FOR SALE OR DISTRIBUTION onto the bone NOTcrystal FOR surface SALE with eventual OR DISTRIBUTION incorporation into the crystal lattice. binding refers to the fraction of total drug in the plasma that is bound to plasma proteins. Many drugs bind to proteins in plasma (Figure 2-7). More than 60 plasma proteins The Blood–Brain Barrier © Jonescan & bind Bartlett to drugs, Learning, but albumin LLCis the most common protein © JonesTh e distribution & Bartlett of drugs Learning, into the central LLC nervous system NOT FORthat SALEdoes so. ORAlbumin DISTRIBUTION is a major carrier for acidic drugs, NOT(CNS) FOR from SALE the blood OR is unique.DISTRIBUTION Th e endothelial cells in the whereas the protein α1-acid glycoprotein binds drugs that capillaries surrounding the brain are packed very tightly are basic in nature. together, which disallows passive transport of materials Th e amount of drug that is bound to plasma proteins in the blood out into the surrounding cerebral tissue. Th is is determined by the drug concentration in the systemic © Jones & Bartlett Learning,blood–brain LLC barrier creates a natural© Jones barrier to& the Bartlett exchange Learning, LLC circulation, the affi nity of the binding sites on the protein of drugs between the blood and the brain.8,9 A drug must be NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION for the drug, and the number of binding sites. Th is concept able to travel through the endothelial cells to penetrate this is important because only the unbound (free) drug can barrier. In the rest of the body, the drug is often able to pass distribute to its intended site of action in tissue; a drug’s between endothelial cells because the cells are not joined as physiologic eff ect is related to the free concentration rather tightly. For a drug to be able to pass into the brain, it must than the© total Jones circulating & Bartlett plasma Learning,drug concentration. LLC Th e be highly lipophilic;© Jones the more & Bartlett lipophilic aLearning, drug is, the moreLLC binding NOTof drug FOR to protein SALE is readily OR DISTRIBUTION reversible, lasting only likely it is to passNOT through FOR the SALE blood–brain OR DISTRIBUTION barrier. a half of a millisecond, and the drug continually shifts from Another natural drug barrier is the placenta. Funda- bound to unbound status.6 Binding sites are limited, how- mentally, the placenta is the organ of exchange between ever, so they may eventually become saturated. When this the mother and fetus. Th e placenta was once viewed as an phenomenon occurs, the risk for drug toxicity increases. absolute barrier to drugs and an agent of protection for the © JonesFor & drugs Bartlett that areLearning, normally highlyLLC protein bound, even © Jonesfetus, but & today Bartlett it is well Learning, known that LLC this belief is fl awed. NOT FORsmall SALE changes OR in the DISTRIBUTION extent of binding can produce a large NOTTh e FORfetus isSALE exposed OR to someDISTRIBUTION extent to all drugs taken by change in the amount of unbound drug and, in turn, a large the mother. Lipid solubility, the extent of plasma bind- change in drug eff ect. Factors that can increase or decrease ing, and the degree of ionization of weak acids and bases the amount of protein available for protein-binding include are important general determinants of drug transfer across myocardial infarction, surgery,© Jones neoplastic & Bartlett disease, rheuma- Learning,the LLC placenta. Additionally, transmembrane© Jones & proteins Bartlett that Learning, LLC toid arthritis, renal disorders,NOT liver FOR compromise, SALE ORand burns. DISTRIBUTION function as effl ux transporters areNOT present FOR in theSALE placenta. OR DISTRIBUTION In contrast to drugs that adhere to the protein-bind- Th e export transporters move drugs that diff use into the ing concept, many drugs accumulate in tissues at higher placental cell back out into the maternal circulation and concentrations than in the extracellular fl uids and blood. thereby limit fetal exposure to potentially toxic agents. Th is pattern may be a result of active transport into the Additional information about the use of drugs in preg- tissue, but© Jonesmore commonly & Bartlett it is Learning, a result of tissue LLC bind- nancy can be found© Jones in the &Pregnancy Bartlett chapter. Learning, LLC ing. TissueNOT binding FOR is SALE often reversible. OR DISTRIBUTION When a large frac- NOT FOR SALE OR DISTRIBUTION tion of drug is tissue bound, it may serve as a reservoir Drug Transporters: P-Glycoproteins that prolongs drug action in that same tissue or at a dis- tant site reached through the circulation. Caution must Some cells have transmembrane proteins that transport © Jonesbe &exercised Bartlett when Learning, prescribing LLC drugs that are highly tissue © Jonesdrugs and & otherBartlett chemicals Learning, out of theLLC cell and into the NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 34 7/23/15 9:02 PM Pharmacokinetics 35 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTIONDrug efflux

Extracellular

ATP ADP Pi

Figure 2-8 Drug transporters: P-glycoprotein in intestinal epithelial cell membranes.

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALEcirculation. OR DISTRIBUTIONOne such drug transporter is permeabilityNOT FORTh ese SALE reactions OR are DISTRIBUTION classifi ed as either phase I reactions or glycoprotein (P-gp), which is also known as multidrug phase II conjugation reactions.11 resistance protein 1 (MDR1) or ATP-binding cassette sub- Th e two-step process of phase I and phase II reactions family B member 1 (ABCB1). P-gp, which is encoded by make the drug molecule hydrophilic so the drug can be the ABCB1 gene, functions© Jones as an & effl Bartlett ux transporter. Learning, Fueled LLCexcreted via the kidney. Phase© Jones I reactions & Bartlett include Learning,oxida- LLC by ATP, this transmembraneNOT FOR protein SALE transports OR DISTRIBUTION drugs and tion, hydrolysis, and reductionNOT reactions, FOR SALE which OR generally DISTRIBUTION other xenobiotics out of cells into the extracellular fl uid result in the loss of pharmacologic activity. Phase II conju- (Figure 2-8).10 P-gp is found in the plasma membranes of gation reactions involve conjugation to form glucuronides, organs that aff ect drug absorption (epithelial cells in the acetates, or sulfates. Both types of reactions play a major intestinal tract), drug distribution (CNS, blood–brain role in diminishing the biologic activity of a drug. barrier,© Jones and placenta), & Bartlett drug Learning, metabolism (liver),LLC and drug For most© Jones drugs, metabolism & Bartlett results Learning, in a pharmacologi- LLC eliminationNOT FOR (kidney). SALE Th ORe primary DISTRIBUTION function of P-gp appears cally inactiveNOT compound; FOR SALE however, OR DISTRIBUTIONa few drugs are trans- to be transporting harmful substances out of body tissues formed in the body to metabolites that have pharmacologic and preventing harmful agents from crossing the blood– activity. Th ese drugs are referred to as prodrugs. For exam- brain barrier. P-gp substrates are generally large lipophilic ple, valacyclovir (Valtrex) is not an eff ective antiviral drug, © Jones & Bartlettcompounds. Learning, Some drugs LLC can inhibit or encourage expres-© Jonesbut &its Bartlett active metabolite, Learning, acyclovir, LLC is active against herpes 12 NOT FOR SALEsion of ORP-gp, DISTRIBUTION thereby aff ecting the plasma concentrationNOT of FORviruses. SALE Prodrugs OR DISTRIBUTION are being developed intentionally to the P-gp substrate. improve drug stability, increase systemic drug absorption, Although the clinical implications and role of P-gp and or prolong the duration of drug activity. When drugs are other drug transporters have not been fully elucidated, it is metabolized into inactive metabolites that are excreted, clear they play important roles in drug response. Because all is well. However, drug metabolism may also result in these proteins are polymorphic,© Jones their& Bartlett role is reviewed Learning, further LLCadverse health consequences.© Jones Th erefore, & Bartlett a review ofLearning, these LLC in the PharmacogeneticsNOT and FOR Pharmacogenomics SALE OR DISTRIBUTION chapter. mechanisms is in order. NOT FOR SALE OR DISTRIBUTION

Metabolism The Cytochrome P-450 Enzymes Termination of a drug’s eﬀ ects by the body is achieved via Th e cytochrome P-450 (CYP450) enzyme family is respon- metabolism© Jones and & Bartlettelimination. Learning, Drug metabolism LLC refers to sible for ©the Jones majority & of Bartlett drug metabolism Learning, reactions. LLC13 Th e the processNOT FOR by which SALE a drug OR isDISTRIBUTION chemically converted in the name P-450NOT was FOR chosen SALE because OR these DISTRIBUTION enzymes are bound body to a metabolite. Th is transformation is usually enzy- to membranes within mitochondria or endoplasmic retic- matic, and the enzymes responsible are mainly located in ulum within the cell (cyto) and because they contain a the liver. Other tissues, such as kidney, lung, small intes- heme pigment that absorbs light at a wavelength of 450 nm © Jones & Bartletttine, and skin, Learning, also contain LLC enzymes that metabolize drugs.© Jones when & Bartlettexposed to Learning, carbon monoxide. LLC Each enzyme name NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 35 7/23/15 9:02 PM 36 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORTable SALE2-2 Naming OR Convention DISTRIBUTION for Cytochrome P-450 Enzymes NOTDrug–Drug FOR InteractionsSALE OR DISTRIBUTION Nomenclature Definition Th e function of CYP450 enzymes, can be signifi cantly CYP Cytochrome P-450 enzyme aff ected by the presence of drugs, food, herbs, and even CYP1 Family designation vitamin supplements (Table 2-3). Drug–drug interactions © Jones & Bartlett Learning,refer LLC to a modifi cation of an expected drug© Jones response & Bartlett due to Learning, LLC CYP1A Subfamily A NOT FOR SALE OR DISTRIBUTIONan exposure to another drug or substanceNOT FOR at approximately SALE OR DISTRIBUTION CYPY1A1 Individual enzyme within subfamily the same time. Most commonly, drug–drug interactions CYP1A1*1A Allelic variant of the individual enzyme occur when two drugs are coadministered and are metabolized by the same CYP450 enzyme. Drugs are typically classifi ed as inhibitors or inducers refl ects a© family, Jones subfamily, & Bartlett and then Learning, an individual LLC number © Jones & Bartlett Learning, LLC of CYP450 enzymatic activity. For example, Drug A might (Table 2-2). For example, CYP2D6 is number 6 in the NOT FOR SALE OR DISTRIBUTION inhibit the activityNOT of FOR CYP3A4 SALE and normallyOR DISTRIBUTION metabolizes subfamily “D” in the “2” family.13 Currently, 57 diff erent Drug B. Th is results in an increase in the serum concen- CYP450 enzyme genes have been identifi ed, but only a few tration of Drug B and subsequent risk of toxicity by Drug of these enzymes are responsible for the majority of drug B. Conversely, administration of Drug A may induce more metabolism in humans.14 Th ree types of CYP450 isoforms © Jones & Bartlett Learning, LLC © JonesCYP3A4 &activity Bartlett and increase Learning, the metabolism LLC of Drug B, (CYP1, CYP2, and CYP3) predominate in the metabolism thereby decreasing the serum concentration and the phar- NOT FORof most SALE commonly OR DISTRIBUTION used pharmaceuticals. NOT FOR SALE OR DISTRIBUTION macologic activity of Drug B. Th e eff ect of inducers occurs Th e various ways these enzymes act represents perhaps more slowly than the eff ect of inhibitors because it takes a the most interesting and most important set of processes while to produce more of the relevant CYP enzymes. Since that providers must know to prescribe drugs safely. Each most of these drug–drug interactions are due to CYP450 CYP450 enzyme is encoded© Jones by a specifi & Bartlett c gene, and Learning, each LLC © Jones & Bartlett Learning, LLC enzymes, it is important to determine the identity of the human has two genes that determine expression of enzy- NOT FOR SALE OR DISTRIBUTIONCYP450 enzyme that metabolizesNOT a FORparticular SALE drug, OR to DISTRIBUTION matic activity—one inherited from the individual’s mother research the eff ects of the drug–drug interaction, and to and the other inherited from the individual’s father. When educate individuals when coadministering drugs that are a gene mutation occurs that results in an alternate ver- metabolized by the same enzyme.12 sion of the gene, the genes are referred to as alleles. Sev- © Jones & Bartlett Learning, LLC Coadministering© Jones drugs & with Bartlett known Learning,drug–drug inter- LLC eral alleles or variants of one gene may exist. When more actions is sometimes done intentionally. An example of than 1%NOT of the FOR population SALE has OR naturally DISTRIBUTION occurring vari- NOT FOR SALE OR DISTRIBUTION intentional coadministration can be found in the treatment ant alleles, the variations are collectively referred to as of persons who are infected with the human immunodefi - polymorphism. Some polymorphisms produce functional ciency virus (HIV). Ritonavir (Norvir), a strong inhibitor of changes in the protein product of that gene. Th e genes that CYP3A4 and CYP2D6, is commonly coadministered with encode CYP450 enzyme activity, for example, are poly- © Jones & Bartlett Learning, LLC © Jonesatazanavir & (Reyataz), Bartlett thereby Learning, increasing LLC plasma levels and morphic. Th us, the clinical expression and functional abil- NOT FOR SALE OR DISTRIBUTION NOTthe FORanti-HIV SALE activity OR of DISTRIBUTIONatazanavir. Th e ritonavir acts to ity of CYP450 enzymes to metabolize specifi c drugs ranges boost the atazanavir concentration in the body. from absent to highly effi cient depending on which alleles Two diff erent drugs can also be put together in one of the specifi c CYP450 gene an individual has inherited.15 combination formulation to minimize drug interactions Th e allele type is noted in the name following an aster- and facilitate patient adherence. Individuals with HIV and isk. Th us, for example, CYP2C19*3© Jones is & a thirdBartlett allele Learning,variant LLC © Jones & Bartlett Learning, LLC acquired immunodefi ciency syndrome (AIDS) were pre- of CYP2C19. NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION scribed a medication regimen that required taking 30 med- In addition, there are genetic, racial, and sex diff erences ications daily prior to the development of highly active in CYP450 activity. Th ese variations are reviewed in more antiretroviral therapy combination drugs; the combination detail in the Pharmacogenetics and Pharmacogenomics drugs now allow them to take signifi cantly fewer pills. chapter. © Jones & Bartlett Learning, LLC Drug–drug© interactions Jones & can Bartlett also occur Learning, when two drugs LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Drug Interactions are given concomitantly and interact via their pharmacokinetic or pharmacodynamic processes. For example, Drugs can interact with many other substances, such as additive eff ects of drugs that cause CNS sedation can, at other drugs, herbs, and nutrients. Th ese interactions can the extreme, cause unconsciousness. When phenytoin © Joneshave & importantBartlett pharmacotherapeuticLearning, LLC consequences. © Jones(Dilantin) & is Bartlettgiven with Learning,salicylates (e.g., LLC aspirin), the plasma NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 36 7/23/15 9:02 PM Pharmacokinetics 37 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALETable 2-3 OR Examples DISTRIBUTION of CYP450 Enzymes That Frequently MetabolizeNOT DrugsFOR and SALE Their PharmacologicOR DISTRIBUTION Eﬀ ectsa

Inhibitorsb: Inducersc: Substratesd: Generic (Brand) Generic (Brand) Generic (Brand) CYP1A2 Fluoroquinolones: ciprofl© oxacin Jones (Cipro), & BartlettCarbamazepine Learning, (Tegretol), LLC insulin, Antidepressants:© Jones amitriptyline & Bartlett (Elavil), Learning, LLC clarithromycin (Biaxin) phenobarbital (Luminal), clomipramine (Anafranil), clozapine (Clozaril), Combination oral contraceptivesNOT FOR SALE phenytoinOR DISTRIBUTION (Dilantin), desipramineNOT (Norpramin), FOR SALEfl uvoxamine OR (Luvox), DISTRIBUTION Other: amiodarone (Cordarone), primidone (Mysoline), imipramine (Tofranil) cimetidine (Tagamet), rifampin (Rifadin), Antipsychotics: haloperidol (Haldol) erythromycin (E-Mycin), tobacco Other: acetaminophen (Tylenol), caff eine, fl uvoxamine (Luvox), isoniazid (INH) theophylline (Theo-Dur) CYP2C9© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Anti-infectives: fl uconazole (Difl ucan), Carbamazepine (Tegretol), Carvedilol (Coreg), celecoxib (Celebrex), isoniazidNOT (INH), FOR SALE OR DISTRIBUTIONphenobarbital (Luminal), NOT FORdiazepam SALE (Valium), OR glipizide DISTRIBUTION (Glucotrol), metronidazole (Flagyl), phenytoin (Dilantin), glyburide (Micronase), ibuprofen (Advil, Motrin), ritonavir (Norvir), primidone (Mysoline), irbesartan (Avapro), losartan (Cozaar) trimethoprim/sulfamethoxazole (Septra) rifampin (Rifadin) Other: amiodarone (Cordarone), © Jones & Bartlettcimetidine (Tagamet), Learning, LLC © Jones & Bartlett Learning, LLC fl uoxetine (Prozac), fl uvoxamine (Luvox) NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION CYP2C19 Fluoxetine (Prozac), Carbamazepine (Tegretol), Omeprazole (Prilosec), phenobarbital (Luminal), fl uvoxamine (Luvox), phenobarbital (Luminal), phenytoin (Dilantin) isoniazid (INH), phenytoin (Dilantin), modafi nil (Provigil) , rifampin (Rifadin) omeprazole (Prilosec), © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC ritonavir (Norvir), NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION topiramate (Topamax) CYP2D6 Amiodarone (Cordarone), No signifi cant inducers Antidepressants: amitriptyline (Elavil), cimetidine (Tagamet), clomipramine (Anafranil), diphenhydramine (Benadryl), desipramine (Norpramin), doxepin (Sinequan), fl uoxetine© Jones (Prozac), & Bartlett Learning, LLC © Jonesfl uoxetine& Bartlett (Prozac), Learning,imipramine (Tofranil), LLC paroxetineNOT FOR (Paxil), quinidine,SALE OR DISTRIBUTION NOT FORparoxetine SALE (Paxil), OR venlafaxine DISTRIBUTION (Eff exor) ritonavir (Norvir), sertraline (Zoloft) Antipsychotics: haloperidol (Haldol), risperidone (Risperdal), thioridazine (Mellaril) Beta blockers: carvedilol (Coreg), metoprolol (Lopressor), propranolol (Inderal) Opiates: codeine, tramadol (Ultram) © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning,Other: donepezil LLC (Aricept), ondansetron (Zofran) NOT FOR SALECYP3A4 OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Azole fungals: fl uconazole (Difl ucan), Carbamazepine (Tegretol), Alprazolam (Xanax), amlodipine (Norvasc), itraconazole (Sporanox), St. John’s wort, dexamethasone, atorvastatin (Lipitor), cyclosporine ketoconazole (Nizoral) phenobarbital (Luminal), (Sandimmune), diazepam (Valium), Anti-infectives: clarithromycin (Biaxin), phenytoin (Dilantin), estradiol (Estrace), simvastatin (Zocor), ciprofl oxacin (Cipro), protease inhibitors, sildenafi l (Viagra), verapamil (Calan), erythromycin (E-Mycin),© Jones & Bartlettrifampin Learning, (Rifadin) LLC zolpidem© (Ambien) Jones & Bartlett Learning, LLC isoniazid (INH), NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION metronidazole (Flagyl), ritonavir (Norvir) Other: amiodarone (Cordarone), cimetidine (Tagamet), diltiazem (Cardizem), verapamil© Jones (Calan) & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC

a ThisNOT table FORis not comprehensive SALE OR as newDISTRIBUTION information is being generated on a regular basis.NOT FOR SALE OR DISTRIBUTION b These drugs inhibit the metabolism of substrates by these CYP450 enzymes. c These drugs induce production of the CYP450 enzyme, which causes increased metabolism of the substrate. d The plasma levels of these drugs are increased by inhibitors and decreased by inducers of the specifi c CYP450 enzyme responsible for their metabolism. Source: Data from Lynch T, Pice M. The eff ect of cytochrome P450 metabolism on drug response, interactions, and adverse eff ects. Am Fam Phys. © Jones & Bartlett2007;76:391-396. Learning,15 LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 37 7/23/15 9:02 PM 38 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORlevels SALE of free OR phenytoin DISTRIBUTION increase because the salicylates NOTTable FOR 2-4 Examples SALE of OR Grapefruit DISTRIBUTION Juice–Drug Interactions compete for plasma protein binding. Phenytoin has a very narrow therapeutic index and increased levels can reach Drug: Clinical Eff ect of Increased Serum Concentration Generic (Brand) of Drug When Taken with Grapefruit Juice toxic levels quickly, resulting in ataxia, nystagmus, or Antiarrhythmics increased seizure activity. © Jones & Bartlett Learning,Amiodarone LLC (Cordarone) Thyroid, pulmonary,© Jones or liver & injury; Bartlett cardiac Learning, LLC arrhythmias, prolonged QT syndrome, P-Glycoprotein Drug InteractionsNOT FOR SALE OR DISTRIBUTION bradycardiaNOT FOR SALE OR DISTRIBUTION Quinidine Torsades de pointes P-glycoprotein activity can also be increased or decreased Benzodiazepines by a number of endogenous and environmental stimuli. Diazepam (Valium) Increased CNS depression In a similar fashion to the CYP450 system, some drugs Midazolam (Versed) Increased CNS depression act as substrates© Jones (inducers) & Bartlett and Learning,others as inhibitors LLC of Triazolam (Halcion)© Jones Increased & Bartlett CNS depression Learning, LLC P-glycoproteinNOT FOR expression. SALE ORP-glycoprotein DISTRIBUTION inhibition Calcium-Channel BlockersNOT FOR SALE OR DISTRIBUTION can result in increased plasma levels of a specifi c drug; Felodipine (Plendil) Flushing, peripheral edema, headaches, conversely, P-glycoprotein induction can result in more hypotension, tachycardia rapid metabolism or elimination and decreased plasma Nicardipine (Cardene) Flushing, peripheral edema, headaches, hypotension, tachycardia levels of the drug in question. St. John’s wort is a potent © Jones & Bartlett Learning, LLC © JonesNimodipine & (Nimotop) Bartlett Learning, Flushing, peripheral LLC edema, headaches, inducer of P-glycoprotein; when this herb is given con- NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR hypotension,DISTRIBUTION tachycardia comitantly with digoxin (Lanoxin), the plasma levels Verapamil (Covera-HS) Flushing, peripheral edema, headaches, of digoxin decrease because the augmented intestinal hypotension, tachycardia P-glycoprotein activity eff ectively keeps digoxin out of CNS Depressants the systemic circulation. Buspirone (BuSpar) Increased adverse eff ects of buspirone © Jones & Bartlett Learning,Carbamazepine LLC (Tegretol) Increased adverse© Jones eff ects of& carbamazepine Bartlett Learning, LLC Drug–Nutrient Interactions NOT FOR SALE OR DISTRIBUTIONClomipramine (Anafranil) Increased NOTeff ect of FORclomipramine SALE OR DISTRIBUTION Sertraline (Zoloft) Increased adverse eff ects of sertraline Drug metabolism can also be infl uenced by diet. Previously Statins these interactions were termed drug–food interactions, Atorvastatin (Lipitor) Increased levels of atorvastatin can cause but they are more appropriately termed drug–nutrient rhabdomyolysis interactions© Jones. Nutrients & Bartlett can aff Learning, ect drug bioavailabil- LLC Lovastatin (Mevacor)© Jones Increased & Bartlett levels of lovastatin Learning, can cause LLC rhabdomyolysis ity via twoNOT mechanisms: FOR SALE (1) ORdecreased DISTRIBUTION or delayed oral NOT FOR SALE OR DISTRIBUTION bioavailability via interference with absorption and (2) Pravastatin (Pravachol) Increased levels of pravastatin can cause rhabdomyolysis increased bioavailability via inhibition of CYP3A in the Simvastatin (Zocor) Increased levels of simvastatin can cause cells of the intestinal wall.16 Th is second mechanism rhabdomyolysis increases plasma levels of the drug metabolized by CYP3A Abbreviation: CNS = central nervous system. © Jonesand & can Bartlett precipitate Learning, adverse drug LLC reactions or toxicities.17 © Jones & Bartlett Learning, LLC NOT FORComponents SALE OR DISTRIBUTIONin grapefruits and grapefruit juices NOT FOR SALE OR DISTRIBUTION (naringin and furanocoumarins) are potent inhibitors of Drug–Herb Interactions CYP3A (Box 2-1).16,18,19 Persons who take a medication that has a narrow therapeutic index and is metabolized Drug–herb interactions are particularly diffi cult to assess.22 by CYP3A are more likely© toJones have an & adverse Bartlett drug Learning, reac- Most LLC herbal products obtained over© Jones the counter & Bartlett are consid- Learning, LLC tion if the medication is takenNOT withinFOR 48SALE hours OR of ingest- DISTRIBUTIONered dietary supplements and, therefore,NOT FOR are notSALE regulated OR DISTRIBUTION ing grapefruit juice. Table 2-4 provides a list of drugs as drugs.23-25 Th us, there is wide variation in the pharma- that have a clinically signifi cant interaction with grape- ceutically active compounds in diff erent herbal prepara- fruit juice. tions, and some may include components that are harmful. Another clinically important drug–nutrient interac- Nonetheless, adverse eff ects are known to occur when spe- tion is the© Joneshypertensive & Bartlett crisis that Learning, can occur amongLLC per- cifi c herbs and© drugs Jones are &taken Bartlett concomitantly Learning, with regu-LLC sons takingNOT monamine FOR SALE oxidase OR (MAO) DISTRIBUTION inhibitors while lated medications.NOT Individuals FOR SALE taking OR warfarin DISTRIBUTION (Coumadin) eating a diet of protein-rich foods that are high in tyra- can have increased bleeding if they take Salvia miltiorrhiza mine (often foods that are aged, fermented, pickled, or (Danshen) or garlic preparations. smoked). Table 2-5 lists additional important drug–nutri- Some of the most well-known herb–drug interactions 20,21 27 © Jonesent & interactions. Bartlett Learning, LLC © areJones associated & Bartlett with use Learning, of St. John’s LLCwort. Th is herb has NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 38 7/23/15 9:02 PM Pharmacokinetics 39 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALETable 2-5 OR Examples DISTRIBUTION of Clinically Important Drug–Nutrient InteractionsNOT FORa SALE OR DISTRIBUTION Drug: Generic (Brand) Foods Mechanism of Action Clinical Implications Angiotensin-converting enzyme High-potassium foods such as ACE inhibitors spare potassium Bradycardia and potential cardiac (ACE) inhibitors bananas, oranges, legumes, meats, so the addition of food high in arrest © Jones salt& substitutesBartlett Learning, LLCpotassium can cause toxicity. © Jones & Bartlett Learning, LLC DigoxinNOT FOR High-fi SALE ber products OR DISTRIBUTIONsuch as bran, Decreases absorption of digoxin.NOT Insuffi FOR cient digoxin SALE eff ect OR DISTRIBUTION pectin, bulk laxatives MAO inhibitors Absolute: aged cheese, aged and Monoamine oxidase found in the GI Severe hypertensive reaction cured meat, sausage, banana peel, tract inactivates tyramine. Tyramine fava bean pods, Marmite or yeast can cause hypertension when © Jones & Bartlett Learning,extracts, sauerkraut, LLC soy sauce, absorbed into© the Jones systemic system.& Bartlett Learning, LLC tap beer NOT FOR SALE OR DISTRIBUTIONModerate: red and white wine, NOT FOR SALE OR DISTRIBUTION bottled or canned beer Quinolones, antifungals, Dairy products, calcium Drugs bind to iron and calcium in Decreased absorption of the and tetracyclines supplements, calcium-fortifi ed the GI tract and form a compound antibiotic orange juice, antacids, iron- that is excreted without entering © Jones & Bartlett Learning, LLC containing vitamins © Jonesthe systemic & Bartlett system. Learning, LLC Theophylline (Theo-Dur) High-fat meal High-fat meals increase absorption Theophylline toxicity: nausea, NOT FOR SALE OR DISTRIBUTION NOT FORof theophylline. SALE OR DISTRIBUTIONvomiting, headache, irritability Warfarin (Coumadin)b Alcohol More than three drinks/day increases eff ect of warfarin Foods with vitamin K must be Large amounts of vitamin K Inadequate anticoagulation used with consistency: broccoli, interfere with the eff ect of warfarin. © Jones Brussels& Bartlett sprouts, turnipLearning, greens, LLC © Jones & Bartlett Learning, LLC NOT FORkale, SALE spinach OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION a This table is not comprehensive as new information is being generated on a regular basis. b Warfarin has multiple drug–drug, drug–nutrient, and drug–herb interactions. Sources: Data from Chen J, Wilkinson J. The monoamine oxidase type B inhibitor rasagiline in the treatment of Parkinson disease: is tyramine a challenge? J Clin Pharmacol. 2012;52:620-62819; Gardner DM, Shulman KI, Walker SE, Tailor SA. The making of a user friendly MAOI diet. J Clin Psychiatry. 25 1996;57:99-104.© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

❚ Box 2-1 The Grapefruit Juice Story © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALEIn 1989, OR a DISTRIBUTION group of researchers used grapefruit juice NOTto mask FOR the taste SALE of alcohol OR DISTRIBUTIONin a study that was evaluating possible interactions between alcohol and felodipine (Plendil), a calcium-channel blocker used to treat hypertension. Thestudy participants developed increases in plasma felodipine levels that were unrelated to alcohol or known felodipine pharmacokinetics. The culprit was the grapefruit juice! Grapefruit has a ©number Jones of &constituents Bartlett thatLearning, inhibit the LLC function of CYP3A4 enzymes© inJones the cells & ofBartlett the intestinal Learning, LLC lumen. Because NOTCYP3A4 FOR metabolizes SALE manyOR DISTRIBUTIONdrugs before they enter the systemic system,NOT inhibition FOR SALE of CYP3A4 OR canDISTRIBUTION cause increased plasma levels of drugs, adverse drug reactions, and/or toxicity. How much grapefruit juice does it take? Is it just the juice or does a grapefruit eaten for breakfast have the same eff ect? What about diff erent types of grapefruit? Here is the story: © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOTGrapefruit FOR juice SALE irreversibly OR DISTRIBUTION inhibits CYP3A4, so new enzymes mustNOT be FOR synthesized SALE beforeOR DISTRIBUTION normal function is restored. Thus, 30% of the inhibitory eff ect is still present 24 hours after ingestion of a single 8-oz glass of normal strength grapefruit juice. It is recommended that medications aff ected by grapefruit juice not be taken until 72 hours after the last glass of grapefruit juice. Unfortunately for grapefruit juice lovers, the eff ect is the same if they drink white, pink, or ruby red juice. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 39 7/23/15 9:02 PM 40 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORpurported SALE eff ORectiveness DISTRIBUTION for the treatment of individuals NOTrenal FOR function SALE will affOR ect DISTRIBUTION drug dose levels. When deciding with depression. However, placebo trials of St. John’s on initial doses for drugs that are eliminated renally, the wort have been inconclusive and meta-analyses have con- individual’s renal function should be assessed. For exam- cluded that it might be eff ective for mild depression only.28 ple, gentamicin (Garamycin) is excreted via the kidney, and In addition, St. John’s wort is an enzyme inducer and it can be toxic to proximal tubule cells. Th erefore, when decreases the plasma levels© ofJones many drugs,& Bartlett including Learning, mid- gentamicin LLC is given in large doses© or Jones for a prolonged & Bartlett period Learning, LLC azolam (Versed), digoxin NOT(Lanoxin), FOR warfarin SALE (Coumadin), OR DISTRIBUTION of time, kidney failure can occur.NOT As theFOR kidney SALE fails, OR less DISTRIBUTION and oral oxycodone.29,30 Women who are taking oral con- gentamicin is excreted, which predisposes the individual to traceptives can also experience breakthrough bleeding additional kidney damage. when St. John’s wort is taken concomitantly with oral contraceptives,© Jones and this & drug Bartlett combination Learning, may interfere LLC with Clearance © Jones & Bartlett Learning, LLC the contraceptive eff ectiveness.29 NOT FOR SALE OR DISTRIBUTION Clearance is theNOT measure FOR of SALEthe body’s OR ability DISTRIBUTION to eliminate a drug.32 Th is measure is often used in pharmacokinetic Drug-Induced Toxicity calculations, and it does not identify the mechanism or Finally, some metabolites of drugs and herbal dietary sup- process of elimination (e.g., the clearance calculation does © Jonesplements & Bartlett are toxic Learning, to the liver LLC or to the kidney.31 In some © notJones consider & Bartlett whether theLearning, drug is eliminated LLC by metabolic NOT FORinstances, SALE tests OR for DISTRIBUTION liver function are required either before NOTprocesses FOR orSALE excretion). OR DISTRIBUTIONTh is measure is the most impor- therapy with a specifi c drug is started or during therapy as tant pharmacokinetic parameter because it determines the a way to monitor liver function. Th e direct toxic eff ects of steady-state concentration for a given dosage route. Th e drugs or their metabolites on liver and/or kidney function mechanisms of drug elimination are complex, but collec- are discussed in more detail in the Drug Toxicity chapter. tively, drug elimination from the body may be quantifi ed © Jones & Bartlett Learning,using LLC the concept of drug clearance.© Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Excretion Drug excretion refers to the elimination of a drug molecule ❚ Pharmacodynamics or its metabolite from the biologic system. Drugs are primarily excreted© Jones via &the Bartlett kidneys, althoughLearning, some LLC excretion Dose–Response© Jones Relationship & Bartlett Learning, LLC does occurNOT via FORsaliva, SALEfeces, sweat, OR DISTRIBUTIONand mammary glands. NOT FOR SALE OR DISTRIBUTION Excretion of drugs in breast milk is important not because Pharmacodynamics is the study of the relationship of the amounts eliminated, but because the excreted drugs between the concentration of a drug in the systemic circu- are potential sources of unwanted pharmacologic eff ects in lation and the biologic response that occurs, often termed the nursing infant. the dose–response relationship. A dose–response curve © Jones &Excretion Bartlett of drugsLearning, and metabolites LLC into urine involves © Jonescan be drawn & Bartlett by plotting Learning, the concentration LLC of the drug NOT FORthree SALE distinct OR processes: DISTRIBUTION glomerular fi ltration, passive NOTon theFOR x-axis SALE and the OR response DISTRIBUTION on the y-axis (Figure 2-9). tubular reabsorption, and active tubular secretion. All Th e minimum eff ective concentration is the lowest dose drugs that have a low molecular weight and are not bound at which a desired response is noted. A corollary concept, to protein are fi ltered in the glomerulus into the glomeru- applied to the eff ect of antimicrobials, is minimum inhibi- lar fi ltrate. Lipid-soluble ©drugs Jones move &back Bartlett into the Learning, blood tory LLC concentration, meaning the© lowest Jones dose & at Bartlett which the Learning, LLC via passive tubular reabsorption, but ionized hydro- antimicrobial inhibits visible growth of a microorganism NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION philic drugs remain in the urine. Some drugs are actively overnight. Th e same dose of a drug often results in diff erent secreted from the circulatory system into the proximal plasma concentrations among individuals. Th is diff erence tubule. Penicillin-G is a good example of a drug that is is secondary to individual diff erences in pharmacokinetic eliminated via tubular secretion. Probenecid (Benemid), parameters. For example, the onset, intensity, and duration which is© sometimes Jones &administered Bartlett Learning,with Penicillin-G, LLC blocks of response an© individual Jones experiences& Bartlett depend Learning, on both LLC the this mechanismNOT FOR and increasesSALE OR plasma DISTRIBUTION levels of penicillin. dose of the drugNOT administered FOR SALE and the OR pharmacokinetics DISTRIBUTION of Finally, the pH of the urine aff ects elimination. the drug in that individual. Weak acids are excreted more easily in alkaline urine Two important parameters can be calculated in draw- and more slowly when the urine is more acidic; the con- ing dose–response relationship curves for particular drugs. © Jonesverse & Bartlettis true for Learning,drugs that are LLC weak bases. Alterations in © JonesPotency is& the Bartlett concentration Learning, at which LLC the drug elicits 50% NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 40 7/23/15 9:02 PM Pharmacodynamics 41 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE ORCLINICAL DISTRIBUTION RESPONSE

TOXIC RANGE

se NOT FOR SALE ORtic- dDISTRIBUTIONo respo NOT FOR SALE OR DISTRIBUTION eu ns p e ra cu e rv h e T Therapeutic effect

dose respon ow- se c L ur ve

© Jones & Bartlettconcentration Plasma Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FORPotential SALE treatment OR DISTRIBUTION MINIMUM EFFECTIVE CONCENTRATION failure

Onset of action Duration of action Temination of action

Figure 2-9 Dose–response curve. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION of its maximal response. Effi cacy is the maximal response Four receptor systems are commonly cited: (1) embedded produced by the drug. A clinical example of a study of enzymes; (2) ligand-binding ion channels; (3) G-protein– pharmacodynamics is recording changes in blood pressure coupled receptors; and (4) the nuclear receptors that are on when a woman is being treated with antihypertensive med- the nuclear or mitochondrial membrane called transcrip- ications. According ©to thisJones concept, & Bartlett there is a drugLearning, receptor LLCtion factors (Figure 2-10). Th© Jonese receptor & of Bartlett a cell membrane– Learning, LLC located within the targetNOT organFOR tissue. SALE When OR aDISTRIBUTION drug mol- embedded enzyme extendsNOT across FOR the cell SALE membrane, OR DISTRIBUTION with ecule fi nds and attaches to the receptor target, it forms a the ligand-binding area located on the cell surface and the complex with that target that causes the biologic response, site for the enzyme activity located on the intracellular por- which is the specifi c mechanism of action of that drug. tion of the receptor. Th e response time of these receptors © Jones & Bartlett Learning, LLC is usually© within Jones seconds. & Bartlett Insulin and Learning, atrial natriuretic LLC fac- Drug–ReceptorNOT FOR SALE Interactions: OR DISTRIBUTION The Role of Cell tor are endogenousNOT FOR ligands SALE that OR aff ectDISTRIBUTION target cells via this Membrane Receptors signaling mechanism. Ligand-binding ion channels are similar to the embedded enzymes, in that the ion channels For a clinician to make rational therapeutic decisions, the cross the cell membrane. Th ese receptors control the fl ow prescriber must understand how drug–receptor interac- of ions into and out of the cell. Th e ligand-binding domain © Jones & Bartletttions underlie Learning, the relationship LLC between dose and response.© Jones is specifi & Bartlett c for a preciseLearning, ion (e.g., LLC calcium). With binding NOT FOR SALEA receptor OR is DISTRIBUTION the cell component that interacts with a drugNOT FORof the SALE ligand ORto the DISTRIBUTION receptor, the channel opens, allowing to produce a psychophysiologic eff ect. Drug receptors are ions to fl ow into or out of the cell. Responses in this system often proteins, and common examples include receptors for commonly occur in milliseconds. Th e neurotransmitter hormones, growth factors, transcription factors, and neu- acetylcholine and the amino acid glycine act through this 33 rotransmitters; the enzymes© Jones that & play Bartlett a role in crucialLearning, meta- LLCreceptor family. © Jones & Bartlett Learning, LLC bolic or regulatory pathways;NOT FOR proteins SALE involved OR in DISTRIBUTION transport; Th e G-protein–coupledNOT receptor FOR family SALE is theOR largest DISTRIBUTION secreted glycoproteins; and structural proteins. Receptors group of cell-surface receptors, and approximately 30% of are the governing agent in determining the dose for any the drugs used today interact with these receptors (Box 2-2). drug. Specifi cally, the affi nity, or propensity of a drug to Th erefore, these receptors are of particular importance bind with a specifi c receptor, determines the drug concen- in pharmacology.34 Th e G-protein–coupled receptor has tration© Jones necessary & Bartlettto achieve Learning,the desired eff LLCect. Drugs have a three parts:© Jones the receptor, & Bartlett the G-protein, Learning, and the LLCeff ector or specifiNOT c affi FOR nity forSALE a particular OR DISTRIBUTION cellular receptor. Drug bind- second messenger.NOT FOR Th SALE ese receptors OR DISTRIBUTION may be located on the ing to the receptor will either increase or decrease the rate cell surface or in a pocket accessible from the cell surface. of the biologic response controlled by that specifi c recep- Ligands bind to the receptors on the exterior portion of the tor. Note that drug–receptor binding does not change the cell membrane. Intracellularly, the bound receptors act as © Jones & Bartlettphysiologic Learning, activity, but simply LLC either enhances or blocks© it.Jonesa catalytic & Bartlett enzyme. Learning, Th e second LLC messenger then interacts NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 41 7/23/15 9:02 PM 42 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION B NOT CFOR SALE OR DISTRIBUTION Agonist drug or andogenous ligand

A © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC G Extractor NOT FOR SALE ORD DISTRIBUTION NOT FOR SALE OR DISTRIBUTION X B Y Cell membrane A Nucleus © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION (A) Embedded enzyme: When a drug binds to the extracellular domain of this receptor, an enzymatic intracellular domain function is activated or inhibited. (B) Ligand-binding ion channel: The drug binds to the extracellular portion of this transmembrane protein complex, which causes it to change shape and alter conductance. (C) G-proteinÐcoupled receptors are also known as seven transmembrane domain receptors. When a drug binds to the extracellular domain of this receptor, a G-protein in the intracellular space is activated to stimulate an effector © Jonesmechanism. & Bartlett (D) Transcription Learning, factor: LLC A lipid-soluble drug crosses the cell© membraneJones &and Bartlett binds to an Learning,intracellular or nuclear LLC receptor. NOT FORFigure SALE 2-10 Four OR receptor DISTRIBUTION types. NOT FOR SALE OR DISTRIBUTION

with intracellular components. Th e G-protein stimulates these receptors stimulate the transcription of messenger the enzyme adenyl cyclase to change ATP to cyclic AMP RNA templates for protein synthesis. With transcription (cAMP) intracellularly, ©with Jones subsequent & Bartlett activation Learning, of factors LLC there is a response time ranging© Jones from & hours Bartlett to days. Learning, LLC protein kinases and cellularNOT reactions. FOR SALEDrugs acting OR DISTRIBUTION via a Steroid hormones, such as estrogenNOT and FOR progesterone, SALE OR act DISTRIBUTION G-protein–coupled receptor include beta blockers and through these intracellular receptor sites.36 antiasthma drugs.35 In contrast, transcription factors are intracellular recep- Agonists, Partial Agonists, and Antagonists tors that© have Jones a longer & responseBartlett time. Learning, Lipid-soluble LLC ligands © Jones & Bartlett Learning, LLC cross the cell membrane to reach these receptors, which Agonists are drugs that elicit a pharmacologic response NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION are located in the cell nucleus on DNA, where the tran- when interacting with the receptor. Such agents shift scription factors regulate protein synthesis. Activation of the equilibrium between the active and inactive forms

© Jones❚ &Box Bartlett 2-2 Gone Learning, But Not Forgotten:LLC Alfred Gilman © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION In 1941, two births occurred with signiﬁ cance for pharmacology—a book and a boy. In that year, two young researchers at Yale University, physician Louis Goodman and pharmacologist Alfred Gilman, published the ﬁ rst edition of their book, The Pharmacological Basis of Therapeutics. This internationally popular text has endured for more than 7 decades as the “bible” of pharmacology. As of 2011, a dozen editions had been published. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC In the same year, Alfred Gilman and his wife had a son. In honor of their friend and the coauthor of the book, they NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION named him Alfred Goodman Gilman. The younger Gilman went on to obtain both a degree as a physician and a PhD in pharmacology. He later was a contributing editor in the aforementioned prestigious text. But his major claim is his discovery regarding G-proteins. Martin Rodbell had found that guanosine-5’ triphosphate (GTP) was integral to actions within a cell. However, it was Alfred G. Gilman who discovered that the G-proteins actually are the molecular switches© Jones between & activationBartlett ofLearning, receptors on LLC the cell and the actions within© Jones the cell. & Knowledge Bartlett of Learning, G-proteins andLLC cellularNOT activity FOR is anSALE invaluable OR DISTRIBUTIONasset in understanding drug actions and forNOT drug FOR design. SALE For this OR work, DISTRIBUTION Rodbell and Alfred G. Gilman shared the 1994 Nobel Prize in Physiology or Medicine. Thus, two births in 1941 have added immeasurably to knowledge in pharmacology and health care.

9781284078879_CH02.indd 42 7/23/15 9:02 PM Pharmacodynamics 43 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALEof the receptorOR DISTRIBUTION in the direction of the active form:NOT By FORof noncompetitive SALE OR DISTRIBUTIONantagonists is usually irreversible until binding the active form more avidly (i.e., they induce a the drug is inactivated. conformational change in the receptor that leads to a maxi- Th e attractive feature of this model is that it explains mal eff ect), they drive the physiologic response in the direc- inverse agonists rather well. If there is a basal tendency of tion of activation. Insulin and morphine are of examples of the receptor to be in the active (agonist) state, then these drugs that act as receptor© Jones agonists. & Bartlett Affi nity Learning,refers to the LLCactive receptors will demonstrate© Jones a &tonic, Bartlett basal agonistLearning, LLC degree of attractionNOT between FOR a drug SALE and ORreceptor. DISTRIBUTION Drugs eff ect even in the total absenceNOT ofFOR agonist SALE ligands OR binding DISTRIBUTION with high affi nity bind more extensively to the receptor to them. If one adds an inverse agonist with a preference than a drug with less affi nity. A partial agonist is a drug for the inactive receptor, the equilibrium shifts to the left, that elicits a partial pharmacologic response when bound and the tonic agonist eff ect is lessened. Diphenhydramine to ©a specifiJones c receptor. & Bartlett Partial Learning, agonists have LLC only a slightly (Benadryl)© Jonesis an inverse & Bartlett agonist thatLearning, binds to LLChistamine higherNOT affi FOR nity for SALE the active OR receptor DISTRIBUTION than for the inactive receptorsNOT thereby FOR suppressing SALE theOR basal DISTRIBUTION agonist activity. form, so they display some agonist activity and they interfere with the function of a full agonist. Buspirone (BuSpar), Therapeutic Effect which is used to treat general anxiety disorder, is a partial agonist. Agonist–antagonists are similar to partial agonists All pharmacologic responses must have a maximum eff ect. © Jones & Bartlettin that they Learning, have an eff ect LLC that is not as potent as full ago-© JonesTh e& maximum Bartlett eff Learning, ect, also referred LLC to as the ceiling eff ect, NOT FOR SALEnist stimulation. OR DISTRIBUTION Th ese drugs aff ect receptors that haveNOT dif- FORis defi SALE ned as ORthe pointDISTRIBUTION at which no further response is ferent forms, and they act as an agonist at one form and as achieved regardless of increasing drug concentration. If an antagonist at another. Butorphanol (Stadol), for exam- the clinician increases the dose of a drug but this does not ple, blocks the eff ect of morphine at the mu opioid receptor lead to further clinical response, it is likely that the maxi- but stimulates the kappa© Jones opioid & receptor; Bartlett the Learning, net result is LLCmum eff ect has been reached.© Jones Th ere is& one Bartlett other possible Learning, LLC analgesia that is notNOT as potent FOR as SALEthe eff ect OR obtained DISTRIBUTION with explanation: Some target organsNOT mayFOR be SALEmore or ORless sensi-DISTRIBUTION morphine. tive to the drug being administered. Th erefore, it is impor- An antagonist is a drug that inhibits the action of an tant to note the drug dose required for the therapeutic agonist when bound to the receptor and has no eff ect eff ect. For some drugs, there is a narrow therapeutic on the agonist itself. Antagonists may have a high affi n- range (or therapeutic window). Th e therapeutic range is ity© for Jones the receptor, & Bartlett but they Learning, do not activate LLC the receptor the plasma© Jonesconcentration & Bartlett of the Learning,drug that produces LLC the whenNOT bound FOR to SALEit. Although OR DISTRIBUTIONantagonists do not initiate a desired actionNOT withoutFOR SALE toxicity. OR Hence, DISTRIBUTION a therapeutic range response, they prevent activation of the receptor by an ago- is between a minimal eff ective drug dose and the toxic con- nist and, therefore, have a pharmacologic eff ect. Th e physi- centration. Lithium (Eskalith), a drug frequently prescribed ologic response to drugs acting as antagonists depends on for women with bipolar disorder, has a narrow therapeutic © Jones & Bartlettthe presence Learning, of an agonist. LLC For example, antihistamines© Jones range & ofBartlett 0.6–1.2 mEq/LLearning, with toxic LLC concentrations at serum and naloxone (Narcan) are examples of antagonists. levels higher than 1.5 mEq/L. NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Antagonists can be competitive or noncompetitive. Drugs also must be evaluated for the therapeutic index A competitive antagonist occurs when the antagonist has (Figure 2-11). Th e therapeutic index is the ratio of lethal

equal affi nity for both the active and inactive conformations doses in 50% of the population (LD50) over the median 6 of the receptor and competes with an agonist for binding minimum eff ective dose (ED50) in 50% of subjects. Th us, to the active form of© the Jones receptor. & BartlettLigands with Learning, the high- LLCthe therapeutic index is ©a Jonesquantitative & Bartlett measure Learning,of the LLC est affi nity will bindNOT with theFOR receptor. SALE If thereOR DISTRIBUTIONis an equal safety of a drug. A drug hasNOT a narrowFOR SALEtherapeutic OR indexDISTRIBUTION affi nity, then the ligand in the highest concentration will if the diff erence between the minimum eff ective concen- bind with the receptor. In contrast, noncompetitive antag- tration and the minimum toxic concentration is less than onists bind with a part of the receptor away from the usual twofold. Th e FDA has named approximately 25 drugs as site© toJones which an& Bartlettagonist binds. Learning, Th is causes LLC a structural or having a© narrow Jones therapeutic & Bartlett index Learning, (Table 2-6). LLC A drug is functional change in the receptor that inactivates it, so ago- safer when the value of the therapeutic index is higher. NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION nist binding at the usual site fails to stimulate the expected Lower therapeutic index numbers are associated with an physiologic response. Th e response to competitive antago- increased risk of toxicity. nists is reversible, in that large enough amounts of the ago- Identifi cation of the therapeutic index sets the stage for nist may surmount the inhibitory eff ect, whereas the eff ect considering bioequivalence. Bioequivalence is determined © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 43 7/23/15 9:02 PM 44 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC 100 NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Therapeutic Efficacy Toxicity window 80 Therapeutic 60 index © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC TI = ED50/LD50 NOT40 FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

20 Percent individuals responding Percent 0 © Jones & Bartlett0 Learning,42 648 101214161820222426283032343638 LLC © Jones & Bartlett0 Learning, LLC NOT FOR SALE OR DISTRIBUTION Dose mg NOT FOR SALE OR DISTRIBUTION

ED50 LD50 % of persons with therapeutic effect at does 6-19 mg % of persons dead at doses of 18-40 mg © Jones & Bartlett Learning, LLC % requiring dose to© achieve Jones desired & effectBartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION % requiring dose forNOT a lethal FOR effect SALE OR DISTRIBUTION Figure 2-11 Therapeutic index.

by comparing the mean bioavailability of two drug products depends on multiple individual factors. For example, an in multiple samples (individuals).© Jones If the & mean Bartlett bioavailability Learning, elderly LLC woman with renal compromise© Jones may & have Bartlett a phar- Learning, LLC of one drug is within 80% NOTto 125% FOR of another SALE drug, OR the DISTRIBUTION two macodynamic proﬁ le that allowsNOT her FORto metabolize SALE ORone DISTRIBUTION are determined to be bioequivalent and can usually be sub- formulation of digoxin (Lanoxin) to obtain a therapeutic stituted for each other. However, bioequivalence does not plasma level, but another formulation may result in sub- guarantee therapeutic equivalence, because bioavailability therapeutic plasma levels. If the prescriber does not want © Jones & Bartlett Learning, LLC the pharmacy ©to Jonessubstitute & one Bartlett drug for Learning, another that LLC has been determined to be bioequivalent, the words “no sub- Table 2-6 NOT Drugs withFOR a Narrow SALE Therapeutic OR DISTRIBUTION Index NOT FOR SALE OR DISTRIBUTION stitution” must be written on the prescription. Drug: Drug: When drugs with a narrow therapeutic index are being Generic (Brand) Generic (Brand) administered intravenously, the trough level should be Amphotericin B (Amphotec) Lithium (Eskalith) drawn just before the next dose. In contrast, when gen- © JonesAminophylline & Bartlett Learning, MetaproterenolLLC sulfate (Alupent) © Jonestamicin sulfate& Bartlett (Garamycin) Learning, is being LLC administered, blood NOT FORCarbamazepine SALE OR (Tegretol) DISTRIBUTION Minoxidil (Rogaine) NOTlevels FOR are obtainedSALE OR for peakDISTRIBUTION levels 30 minutes after the Clindamycin (Cleocin) Phenytoin sodium (Dilantin) intravenous infusion ends and trough levels are obtained just before the next dose. Th e drug dose may be adjusted Clonidine (Catapres) Prazosin hydrochloride (Minipress) according to the levels obtained. Peak and trough levels Digoxin (Lanoxin) Primidone (Mysoline) vary with the drug. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Dimercaprol Procainamide hydrochloride NOT(Procanbid) FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Ethinyl estradiol/progestin Quinidine sulfate oral contraceptives ❚ Pharmacotherapy Guanethidine sulfate Theophylline (Theo-Dur) Gentamicin (Garamycin) Tricyclic antidepressants Pharmacotherapeutics refers to the clinician apply- © Jones & Bartlett Learning, LLC ing knowledge© of Jones the beneﬁ & Bartlettts and risks Learning, of drug therapy LLC Isoproterenol sulfate (Isuprel) Warfarin (Coumadin) NOT FOR SALE OR DISTRIBUTION to individual NOTcare. In FOR addition SALE to pharmacokineticsOR DISTRIBUTION and Levothyroxine (Synthroid) Valproic acid (Depakene) pharmacodynamics, other determinants of drug therapy Source: Data from Food and Drug Administration, Center for Drug include the age or gender of the person receiving the drugs, Evaluation and Research. past and present health status, family history, lifestyle © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 44 7/23/15 9:02 PM Pharmacotherapy 45 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALEbehaviors, OR and DISTRIBUTION drug compliance. All of these factors mustNOT FORor excreted SALE as OR eff ectivelyDISTRIBUTION due to the immature liver and be considered when selecting and monitoring drug therapy. kidneys, respectively. Likewise, older women may require Understanding pharmacokinetics and pharmacodynamics a decreased dose and are at greater risk for toxicity due is an important component of pharmacotherapy given the to the decreasing effi ciency of hepatic metabolism and goal of achieving a desired benefi cial eff ect with minimal excretion associated with aging of the hepatic and renal adverse eff ects. Th e© pharmacokinetic Jones & Bartlett processes Learning, of absorp- LLCsystems. Th e lowered level© Jonesof enzyme & Bartlettactivity slows Learning, the LLC tion, distribution, metabolism,NOT FOR andSALE excretion OR DISTRIBUTION determine rate of drug metabolism causingNOT FORhigher SALEplasma drugOR levelsDISTRIBUTION how rapidly, in which concentration, and for how long per dose compared to young adults. Also, certain diseases the drug will be present at the target organ. Th e pharma- that cause impaired renal and liver function mandate dos- codynamic concepts of maximum response, therapeutic age adjustments. index,© Jones and drug-receptor & Bartlett interactions Learning, determine LLC the mag- © Jones & Bartlett Learning, LLC nitudeNOT of FORthe eff ectSALE at a particular OR DISTRIBUTION concentration. Knowing Gender DifferencesNOT FOR in SALE Drug Metabolism OR DISTRIBUTION the relationship between drug concentrations and eff ects Gender diff erences in drug metabolism may relate to sev- allows the clinician to take into account the various fea- eral factors. Women are generally smaller in stature and tures of an individual that make this person diff erent from weight than men; consequently, when women are pre- the average individual in response to a drug. © Jones & Bartlett Learning, LLC © Jonesscribed & Bartlett the standard Learning, dose for men, LLC they are often found to NOT FOR SALEChronobiology/Chronopharmacology OR DISTRIBUTION NOT FORhave SALEhigher plasma OR DISTRIBUTION drug concentrations. In addition, individual diff erences in water and fat content can aff ect drug Chronobiology or chronopharmacology is the study of metabolism, as some drugs are more hydrophilic or lipo- pharmacokinetics as related to circadian rhythms or tem- philic. Women have a slower gastrointestinal transit time poral changes. Variations in metabolism may diff er by time during the luteal phase of the menstrual cycle and during of day, as well as by ©the Jones age of the & individual.Bartlett Learning,In particular, LLCpregnancy, which can also© aff Jonesect drug &absorption. Bartlett Women Learning, LLC elderly individuals NOTmay evidence FOR SALE changes OR in metabolismDISTRIBUTION have a 50% to 75% higherNOT risk for FOR having SALE an adverse OR DISTRIBUTIONdrug associated with time of day.37 It has been suggested that use events as men, in large part due to these many gender- of drugs may be safer as well as more eff ective if timing of related physiologic variations.36 drug administration is considered.38 Metabolic diff erences between the sexes have been ©Timing Jones of administration& Bartlett Learning, of antihypertensives LLC at bed- noted for© aJones number & ofBartlett drugs. ThLearning, is suggests LLCthat hor- time,NOT for FORexample, SALE may result OR inDISTRIBUTION better blood pressure con- monal activityNOT mightFOR affSALE ect the OR activity DISTRIBUTION of certain CYP450 trol.39 Intriguing chronopharmacology studies have also enzymes—a topic discussed in more detail in the Phar- been conducted regarding the use of aspirin during preg- macogenetics and Pharmacogenomics chapter. For nancy. One randomized controlled trial compared changes example, women metabolize diazepam (Valium), prednis- in blood pressure in women who took a placebo or low-dose olone (Deltasone, Orapred), caff eine, and acetaminophen © Jones & Bartlettaspirin at one Learning, of three times: LLC in the morning, 8 hours after© Jones (Tylenol) & Bartlett slightly Learning, faster than LLCtheir male counterparts. NOT FOR SALEawakening, OR orDISTRIBUTION at bedtime. Blood pressure was signifi cantlyNOT FORConversely, SALE men OR metabolize DISTRIBUTION propranolol (Inderal), chlor- reduced in the women who took aspirin compared to those diazepoxide (Librium), lidocaine, and some steroids faster who took the placebo only when the aspirin was taken 8 than women. hours after awakening and at bedtime. Low-dose aspirin had no eff ect on blood pressure if taken in the morning.40 Health Status © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Th ese fi ndings underscore the need for more studies in the Both illness and some normal changes in health status can area of chronopharmacology.NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION aff ect the pharmacokinetics and pharmacodynamics of a The Effects of Age given drug. During pregnancy, a woman’s reduced gastrointestinal motility and increased gastric pH aff ect drug Clearly, a number of factors related to drugs infl uence absorption. Drug distribution may change because the © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC drug dose, absorption, and effi cacy; however, numerous maternal plasma volume increases by 50% in pregnancy. factorsNOT related FOR toSALE the biologic OR DISTRIBUTION system also infl uence drug Serum albuminNOT FOR binding SALE capacity OR is decreasedDISTRIBUTION during preg- therapy.37 Newborns and children generally require lower nancy, which results in an increase in unbound, active drug doses secondary to their size and their immature drug. Maternal hormones can aff ect drug metabolism hepatic and renal systems. Drugs cannot be metabolized by enhancing or inhibiting metabolism of various drugs. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 45 7/23/15 9:02 PM 46 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORDrug SALE excretion OR may DISTRIBUTION also be aff ected due to the increase NOTIndividuals FOR SALE should OR also DISTRIBUTION be questioned about their use in renal blood fl ow. Pharmacokinetic and pharmacody- of illegal substances. Th e use of illegal substances in addi- namic changes in pregnancy are discussed further in the tion to prescribed medications can result in acute toxicity. Pregnancy chapter. When a person who is taking heroin takes a barbiturate, A woman with liver disease and tuberculosis will be for example, the combined sedative eff ect can result in a unable to take some antitubercular© Jones & drugs Bartlett due toLearning, their coma. LLC Appropriate treatment is© contingent Jones & upon Bartlett the cor- Learning, LLC hepatic toxicity. CongestiveNOT heart FOR failure SALE decreases OR hepatic DISTRIBUTION rect identifi cation of the toxic substance.NOT FOR Illegal SALE drug OR use DISTRIBUTION blood fl ow by reducing cardiac output, which alters the is found in every age group, ethnicity, and socioeconomic extent of drug metabolism. status, so all individuals should be questioned about this An alteration in production of the major drug-bind- practice. ing protein,© Jones albumin, & canBartlett also alter Learning, the ratio of LLC bound to © Jones & Bartlett Learning, LLC unboundNOT drug. FOR Th us, SALE a decrease OR in DISTRIBUTION plasma albumin can The Role of PolypharmacyNOT FOR SALE OR DISTRIBUTION increase the fraction of unbound (free) drug, which then Although there is no specifi c number of diff erent drugs at becomes available to exert more of a pharmaceutical eff ect. which polypharmacy is universally defi ned, most studies Th e reverse is true when plasma albumin increases. have used fi ve as the number of concurrently taken drugs 39 © JonesGenetic & Bartlett Factors Learning, LLC © Jonesthat defi nes & Bartlettpolypharmacy. Learning, When aLLC person is taking sev- NOT FOR SALE OR DISTRIBUTION NOTeral FORmedications SALE due OR to DISTRIBUTION multiple medical problems, the Drug action can vary as a result of genetic factors, a consid- chance that a drug–drug interaction will occur increases. eration discussed in more detail in the Pharmacogenetics Because individuals may take several medications at a time and Pharmacogenomics chapter. Essentially, the metabo- and fail to report each one to their varied healthcare provid- lism rate for certain drugs can be slower or faster in some ers, the potential for drug–drug interactions can be high.43 individuals based on genetic© Jones determinants. & Bartlett Some Learning, indi- LLC © Jones & Bartlett Learning, LLC viduals are poor metabolizersNOT FORof certain SALE drugs OR because DISTRIBUTION Drug Adherence NOT FOR SALE OR DISTRIBUTION a specifi c CYP450 enzyme’s activity is slower in those Pharmacoadherence is the extent to which a person individuals compared to most persons in the general pop- adheres to a medication regimen as mutually agreed upon ulation.41 Slower metabolism of drugs places these indi- with a healthcare professional.44 Studies have found that viduals at increased risk for adverse drug reactions and © Jones & Bartlett Learning, LLC 20% to 80% of© individuals Jones &with Bartlett chronic Learning,conditions requir- LLC drug toxicity. NOT FOR SALE OR DISTRIBUTION ing long-term NOTpharmacologic FOR SALE regimens OR do DISTRIBUTION not follow the Lifestyle Behaviors prescribed regimen.45 Measures of pharmacoadherence include direct, indirect, and subjective indexes. Direct Lifestyle behaviors also are linked to pharmacodynam- measures may include biochemical assays as serum iron ics and pharmacokinetics. For example, a woman who or total iron binding capacity levels for individuals with © Jonesis &prescribed Bartlett a Learning,barbiturate—a LLC drug that causes seda- © Jonesiron-defi ciency& Bartlett anemia Learning, who are prescribed LLC ferrous sulfate NOT FORtion SALEand drowsiness—and OR DISTRIBUTION who also ingests alcohol may NOT(Feosol). FOR Indirect SALE measures OR DISTRIBUTION would include pill counts. Tai- have a drug–drug interaction that will enhance the seda- loring health education in accordance with the individual’s tive eff ect. Th erefore, individuals need to be questioned culture, health literacy, and health numeracy may help frequently and directly with exacting questions such as improve pharmacoadherence. Health education is only one “How much alcohol do you© drinkJones per day,& Bartlett and what Learning,do you piece LLC to this puzzle. Access to ©drugs Jones and fi &nancial Bartlett ability Learning, LLC drink?” rather than “Do youNOT drink FOR alcohol?” SALE Women OR DISTRIBUTION also to pay for drugs can also adverselyNOT aff ectFOR pharmacoadher- SALE OR DISTRIBUTION need to be carefully questioned regarding self-medication ance. Th us many factors need to be assessed when pharma- with over-the-counter drugs, herbs, and dietary supple- coadherance appears problematic. ments. Any and all of these substances may interfere with a prescribed drug’s eff ectiveness. For example, a pregnant woman ©with Jones nausea & and Bartlett vomiting Learning, may self-medicate LLC with © Jones & Bartlett Learning, LLC the herbNOT ginger. FOR Generally SALE in ORsmall DISTRIBUTION and moderate doses, ❚ ConclusionNOT FOR SALE OR DISTRIBUTION ginger may be helpful for some pregnant women; in pregnant women who are at high risk for hemorrhage, however, According to the Institute of Medicine, in any 7-day period, ginger inhibits platelet aggregation, thereby increasing 4 out of 5 adult individuals in the United States take pre- 42 © Jonestheir & potentialBartlett for Learning, bleeding. LLC © Jonesscription &medications, Bartlett Learning,over-the-counter LLC medications, and NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 46 7/23/15 9:02 PM References 47 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC 46 NOT FOR SALEsupplements. OR DISTRIBUTION In this organization’s report PreventingNOT FOR SALE OR DISTRIBUTION Medication Error: Quality Chasm Series, medication ✜ References errors were found to be a signifi cant cause of morbid- ity and mortality. Providers of women’s health care have 1. Guittierrez K. Pharmacotherapeutics. 2nd ed. St. Louis: a responsibility to understand the pharmacokinetics and Saunders Elsevier; 2008: 44. pharmacodynamics© of Jones the drugs & Bartlettthey order Learning, or adminis- LLC2. Berman A. Reducing© Jonesmedication & Bartlett errors through Learning, LLC ter. Multiple factorsNOT need toFOR be considered, SALE OR including DISTRIBUTION age, naming, labeling, andNOT packaging. FOR SALEJ Med Syst.OR 2004;DISTRIBUTION gender, ethnicity, underlying health status, lifestyle behav- 28:9-29. iors that infl uence a drug’s action, and eff ects. Routes 3. Gavhane YN, Yadav AV. Loss of orally adminis- and timing of drug administration vary depending on the tered drugs in GI tract. Saudi Pharm J. 2012;20(4): drug© Jonesand the &woman’s Bartlett general Learning, health status.LLC Monitor- 331-344.© Jones & Bartlett Learning, LLC 4. Soderberg Lofda K, Andersson M, Gustafsson L. ingNOT for drug FOR interactions SALE OR with DISTRIBUTION nutrients, herbs, and other NOT FOR SALE OR DISTRIBUTION drugs46 and drug reactions is an important intervention. In Cytochrome P450-mediated changes in oxycodone addition, drug administration and responses vary across pharmacokinetics/pharmacodynamics and their clini- the lifespan, such that women who are pregnant, lactat- cal implications. Drugs. 2013;73:533-543. ing, young, or elderly require special vigilance. Health 5. Gao Y, Shao J, Jiang Z, et al. Drug enterohepatic circula- © Jones & Bartletteducation Learning,requires assessment LLC of literacy, knowledge,© Jones &tion Bartlett and distribution: Learning, constituents LLC of systems pharma- NOT FOR SALEand concerns, OR DISTRIBUTION as well as the synergy of multidisciplinaryNOT FOR cokinetics.SALE OR Drug DISTRIBUTION Discovery Today. 2014;19(3):326-340. healthcare members working together to provide the best 6. Buxton ILO, Benet LZ. Pharmacokinetics: the dynam- care possible for women. ics of drug absorption, metabolism, and elimination. In: Brunton LL, Chabner B, Knollman B, eds. Goodman © Jones & Bartlett Learning, LLC & Gilman’s the Pharmacological© Jones Basis & Bartlett of Th erapeutics. Learning, LLC 12th ed. New York, NY: McGraw-Hill; 2011:17-40. ✜ ResourcesNOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION 7. Meireles M, Martel F, Araújo J, et al. Characterization Organization Description Website and modulation of glucose uptake in human blood– Indiana University Drug interaction http://medicine brain barrier model. J Membr Biol. 2013;246(9):669-677. School of Medicine table of substrates, .iupui.edu/fl ockhart/ 8. Smith B, Yogaratnam D, Levasseur-Franklin K, Forni A, inhibitors, and table.htm © Jones & Bartlettinducers withLearning, links LLC Fong© J. Jones Introduction & Bartlett to drug pharmacokineticsLearning, LLC in the NOT FOR SALEfrom ORthe drug DISTRIBUTION name criticallyNOT ill FOR patient. SALE Chest. OR 2012;141(5):1327-1336. DISTRIBUTION to a PubMed list 9. Akhtar N, Ahad A, Khar RK, et al. Th e emerging role of citations that is continuously updated of P-glycoprotein inhibitors in drug delivery; a patent Concise Guide to Drug “Drugs” section in the review. Expert Opin Th er Pat. 2011;21(4):561-576. Interaction Principles Lexi-Complete PDA 10. Corsini A, Bortolini M. Drug-induced liver injury: © Jones & Bartlettfor Medical Practice:Learning, software LLC package © Jones &the Bartlett role of Learning,drug metabolism LLC and transport. J Clin NOT FOR SALECytochrome OR P450s, DISTRIBUTION from Lexi-Comp; NOT FOR SALE OR DISTRIBUTION UGTs, P-Glycoproteins this PDA software Pharmacol. 2013;53(5):463-474. includes a section on 11. Li F, Maag H, Alfredson T. Prodrugs of nucleoside cytochrome P-450 analogues for improved oral absorption and tissue enzyme activity for targeting. J Pharm Sci. 2008;97:1109-1134. each drug narrative Merck Manual Online ©Overview Jones of & Bartlettwww.merckmanuals. Learning, LLC12. Krau SD. Cytochrome© P450, Jones part &1: whatBartlett nurses Learning, really LLC Medical Library NOTPharmacokinetics FOR SALE com/professional/ OR DISTRIBUTIONneed to know. Nurs ClinNOT N Am. FOR 2013;48(4):671-680. SALE OR DISTRIBUTION and Overview of clinical-pharmacology/ 13. Wilkinson G. Drug metabolism and variability Pharmacodynamics: pharmacokinetics/ Articles that review overview-of- among patients in drug response. N Engl J Med. the principles of pharmacokinetics 2005;352(21):2211-2221. pharmacokinetics 14. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacoge- © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC with graphs and netics: from bench to byte: an update of guidelines. NOT FOR SALEclinical OR correlates DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Interactive Clinical Interactive colorful www.icp.org.nz Clin Pharmacol Th er. 2011;89(5):662-673. Pharmacology.org descriptions of many 15. Lynch T, Pice M. Th e eff ect of cytochrome P450 metab- pharmacokinetic and olism on drug response, interactions, and adverse pharmacodynamic eff ects. Am Fam Phys 2007;76:391-396. concepts © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

9781284078879_CH02.indd 47 7/23/15 9:02 PM 48 CHAPTER 2 Principles of Pharmacology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR16. SALEChan LN. OR Drug–nutrient DISTRIBUTION interactions. J Parenter NOT31. FOR Bunchorntavakul SALE OR C, DISTRIBUTION Reddy K. Review article: herbal Enteral Nutr. 2013;37:450-459. and dietary supplement hepatotoxicity. Aliment 17. Pirmohamed M. Drug–grapefruit juice interactions. Pharmacol Th er. 2013;37:3-17. BMJ. 2013;346:f1. 32. Li R, Barton HA, Varma MV. Prediction of pharma- 18. Seden K, Dickinson L, Khoo S, Back D. Grapefruit– cokinetics and drug–drug interactions when hepatic drug interactions. Drugs.© Jones 2010;70(18):2373-2407. & Bartlett Learning, LLCtransporters are involved. Clin© Jones Pharmacokinet. & Bartlett 2014; Learning, LLC 19. Chen J, Wilkinson J.NOT Th e FORmonoamine SALE oxidase OR DISTRIBUTIONtype B 53(8):659-678. NOT FOR SALE OR DISTRIBUTION inhibitor rasagiline in the treatment of Parkinson dis- 33. Hogg RC, Raggenbass M, Bertrand D. Nicotinic ease: is tyramine a challenge? J Clin Pharmacol. 2012; acetylcholine receptors: from structure to brain 52:620-628. function. Rev Physiol Biochem Pharmacol. 2003;147:1-46. 20. Flockhart© Jones DA. Dietary& Bartlett restrictions Learning, and drug LLC interac- 34. Solinski HJ,© JonesGudermann & Bartlett T, Breit Learning,A. Pharmacology LLC tionsNOT with FOR monoamine SALE oxidase OR DISTRIBUTION inhibitors: an update. and signallingNOT ofFOR MAS-related SALE OR G DISTRIBUTIONprotein-coupled J Clin Psychiatry. 2012;73(suppl 1):17-24. receptors. Pharmacol Rev. 2014;66(3):570-597. 21. Colalto C. Herbal interactions on absorption of drugs: 35. Amezcua-Gutierrez MA, Cipres-Flores FJ, Trujillo- mechanism of action and clinical risk assessment. Ferrara JG, Soriano-Rusua MA. Clinical implica- Pharmacol Res. 2010;62:207-227. tions of recent insights into the structural biology © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC 22. Tsai H, Lin H, Simon Pickard A, Tsai H, Mahady G. of beta2 adrenoreceptors. Curr Drug Targets. 2012; NOT FOR SALEEvaluation OR of DISTRIBUTION documented drug interactions and NOT FOR13(10):1336-1346. SALE OR DISTRIBUTION contraindications associated with herbs and dietary 36. Witley H, Lindsey W. Sex-based diff erences in drug supplements: a systematic literature review. Int J Clin activity. Am Fam Physician. 2009;80(11):1254-1258. Pract. 2012;66(11):1056-1078. 37. Bruguerolle B. Clinical chronopharmacology in the 23. Kennedy DA, Seely ©D. Jones Clinically & basedBartlett evidence Learning, of LLCelderly. Chronobiol Int. 2008;25(1):1-15.© Jones & Bartlett Learning, LLC drug–herb interactions:NOT a systematicFOR SALE review. OR Expert DISTRIBUTION 38. Ohdo S, Koyanagi S, MatsunagaNOT FOR N, SALEHamdan OR A. DISTRIBUTION Opin Drug Saf. 2010;9(1):79-124. Molecular basis of chronopharmaceutics. J Pharm Sci. 24. Sahoo N, Manchikanti P, Dey S. Herbal drugs: stan- 2011;100:3560-3576. dards and regulation. Fitoterapia. 2010;81:462-471. 39. Zhao P, Xu P, Wan C, Wang Z. Evening versus morn- 25. Gardner DM, Shulman KI, Walker SE, Tailor SA. Th e ing dosing regimen drug therapy for hypertension. making© Jones of a user & friendly Bartlett MAOI Learning, diet. J Clin LLCPsychiatry. Cochrane© Database Jones &Syst Bartlett Rev. 2011;10:CD004184. Learning, LLC 1996;57:99-104.NOT FOR SALE OR DISTRIBUTION DOI: 10.1002/14651858.CD004184.pub2.NOT FOR SALE OR DISTRIBUTION 26. Rahimi R, Abdollahi M. An update on the ability 40. Ayala DE, Ucieda R, Hermida RC. Chronotherapy of St. John’s wort to aff ect the metabolism of other with low-dose aspirin for prevention of complications drugs. Expert Opin Drug Metab Toxicol. 2012;8(6): in pregnancy. Chronobiol Int. 2013;30(1-2):260-279. © Jones &691-708. Bartlett Learning, LLC © Jones41. Samer & BartlettCF, Lorenzini Learning, KI, Rollason LLC V, Daali Y, 27. Linde K, Berner MM, Kriston L. St John’s wort for Desmeules JA. Applications of CYP450 testing in the NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION major depression. Cochrane Database Syst Rev. clinical setting. Mol Diagn Th er. 2013;17(3):165-184. 2008;4:CD000448. DOI: 10.1002/14651858.CD000448. 42. Liao YR, Leu YL, Chan YY, Kuo PC, Wu TS. Anti- pub3. platelet aggregation and vasorelaxing eff ects of the 28. Russo E, Scicchitano F, Whalley B, et al. Hypericum constituents of the rhizomes of Zingiber offi cinale. perforatum: pharmacokinetic,© Jones mechanism & Bartlett of Learning,action, LLCMolecules. 2012;17(8):8928-8937.© Jones & Bartlett Learning, LLC tolerability, and clinicalNOT FORdrug–drug SALE interactions. OR DISTRIBUTION 43. Hovstadius B, Petersson G. FactorsNOT FOR leading SALE to excessive OR DISTRIBUTION Phytother Res. 2014;28(5):643-655. polypharmacy. Clin Geriatr Med. 2012;28:159-172. 29. Nieminen T, Hagelberg N, Saari T, et al. St John’s wort 44. Chisholm-Burns MA, Spivey C. Pharmacoadherence: greatly reduces the concentrations of oral oxycodone. a new term for a signifi cant problem. Am J Health- Eur© J Pain.Jones 2010:14:854-859. & Bartlett Learning, LLC Syst Pharm.© Jones2008;65:661-667. & Bartlett Learning, LLC 30. Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. 45. Aronson J, Ferner RE. Clarifi cation of terminology in NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Interaction of St. John’s wort with oral contraceptives: drug safety. Drug Safety. 2005;28(10):851-870. eff ects on the pharmacokinetics of norethindrone and 46. Institute of Medicine. Preventing Medication Errors: ethinyl estradiol, ovarian activity and breakthrough Quality Chasm Series. Washington, DC: Institute of bleeding. Contraception. 2005;71(6):402-408. Medicine; 2006. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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