© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE3 OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC PrinciplesNOT FOR SALE of OR DISTRIBUTION PharmacologyNOT FOR SALE OR DISTRIBUTION Beth© Jones M. Kelsey & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FORc. Placenta SALE has enzymeOR DISTRIBUTION systems that metabolize some drugs, and Pharmacokinetics (Study of How P-glycoprotein that actively transports some drug substrates away from fetal circulation the Body Processes Drugs) 6. Steady state—when rate of drug elimination equals rate of drug availability (absorption) • Absorption © Jones & Bartlett Learning, LLC7. Half-life—time it takes for plasma© concentrationJones & ofBartlett a drug to be Learning, LLC 1. Movement of drug from site of entry into the systemic NOT FOR SALE OR DISTRIBUTIONreduced by 50%; used to determineNOT time FOR required SALE to reach ORsteady DISTRIBUTION circulation state and dosage interval 2. Bioavailability—percentage of active drug that is absorbed and 8. Volume of distribution—apparent volume in which drug is available at the target tissue dissolved; relates to concentration of drug in plasma and the 3. Affected by cell membranes, blood flow, drug solubility, pH amount in the body; may be used to calculate loading dose need of drug,© variablesJones related & Bartlett to the gastrointestinal Learning, tract, LLCdrug to achieve a© desired Jones steady & state Bartlett drug level Learning, immediately LLC concentration, dosage form, route of administration NOT FOR SALE OR DISTRIBUTION • Metabolism NOT FOR SALE OR DISTRIBUTION • Distribution 1. Chemical inactivation of drug by conversion to a more water-soluble 1. Movement of drug into body fluids and body tissues compound (metabolite) that can be excreted from the body 2. Affected by permeability of capillaries and tissues, systemic 2. Chemical alterations are produced by microsomal enzymes mainly © Jones & circulation, Bartlett size Learning,of drug molecule, LLC affinity for lipid and aqueous © Jonesin the & liver Bartlett Learning, LLC tissues, protein binding, and pH NOT FOR SALE OR DISTRIBUTION NOT3. FOR Hepatic SALE first-pass OR effect—orally DISTRIBUTION administered drug goes from 3. Plasma protein binding—drugs may attach to proteins (mainly GI tract through portal system to liver before going to the general albumin) in the blood; only unbound drug is active; as free drug circulation; some metabolism of drug may occur as it is taken up is excreted, more of drug is released from binding to replace by hepatic microsomal enzymes what is lost; competition for binding sites by different drugs 4. Drug interactions can affect metabolism by enzyme induction or and hypoalbuminemia can© affect Jones amount & of Bartlett free drug that Learning, is LLCinhibition © Jones & Bartlett Learning, LLC available NOT FOR SALE OR DISTRIBUTION5. Variation in drug metabolism mayNOT be affected FOR by SALE genetics, ORage, DISTRIBUTION 4. Blood–brain barrier affects drug distribution—endothelial cells pregnancy, liver disease, diet, alcohol, circadian rhythm of capillaries surrounding brain are packed tightly together, which 6. Prodrugs—drugs that must be metabolized to become effective limits passive transport from blood into cerebral tissue; drug must (active metabolites); developed to improve stability, increase be highly lipophilic to pass into brain absorption, or prolong duration of drug activity; that is, valacyclovir 5. Placental© Jones barrier affects & Bartlett drug distribution Learning, LLC is not effective,© Jones but its active & Bartlettmetabolite, acyclovir,Learning, is LLC a. Several layers of placental tissue separate maternal and fetal NOT FOR SALE OR DISTRIBUTION • Excretion NOT FOR SALE OR DISTRIBUTION circulation, so the placenta is not an absolute barrier to drugs; almost all drugs taken by mother pass through placenta to 1. Removal of drug from body via the kidneys, intestines, sweat and fetus to some degree, and they reach steady state levels in fetus salivary glands, lungs, or mammary glands between 50% to 100% of maternal concentration 2. Urinary excretion—net effect of glomerular filtration, active © Jones &b. BartlettGeneral determinants Learning, of drug LLC transfer across placenta include © Jones tubular & secretion,Bartlett and Learning, partial reabsorption LLC NOT FOR SALElipid solubility, OR DISTRIBUTION extent of plasma protein binding, and degree of NOT3. FOR Enterohepatic SALE recirculation—some OR DISTRIBUTION fat-soluble drugs may be reabsorbed ionization of weak acids and bases into the bloodstream from the intestines and returned to the liver 28 © Jones & Bartlett Learning, LLC. NOT FOR SALE OR DISTRIBUTION. 9781284126662_CH03.indd 28 16/02/17 3:16 PM Drug Contraindications 29 • Pharmacokinetic changes during pregnancy 3. Gender © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC 1. Absorption—not significantly affected 4. Pathologic state NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION 2. Distribution 5. Circadian rhythm a. Increase in plasma volume may result in lower serum levels of drug 6. Genetic factors b. Reduction in plasma proteins (albumin) may result in higher 7. Psychologic factors levels of free (unbound) drug • Unpredictable types include: 3. Metabolism © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC 1. Drug allergy a. Hepatic enzyme systemsNOT (e.g., FOR CYP3A4, SALE CYP1A2) OR areDISTRIBUTION affected NOT FOR SALE OR DISTRIBUTION by rising levels of estrogen and progesterone and may result in 2. Idiosyncrasy either faster or slower metabolism of some drugs 3. Tolerance b. Blood flow through the liver is not changed significantly so 4. Drug dependence there is no change in first-pass effects © Jones & Bartlett Learning, LLC • Iatrogenic© responses Jones include: & Bartlett Learning, LLC 4. Excretion—increase in glomerular filtration rate (GFR) may result 1. Blood dyscrasias inNOT faster eliminationFOR SALE of drugs OR excreted DISTRIBUTION primarily through the NOT FOR SALE OR DISTRIBUTION kidneys 2. Hepatic toxicity 3. Renal damage 4. Teratogenic effects © Jones &Pharmacodynamics Bartlett Learning, LLC (Study of © Jones5. &Dermatologic Bartlett effects Learning, LLC NOT FORMechanism SALE OR DISTRIBUTION of Drug Action on Living NOT FOR SALE OR DISTRIBUTION Tissue) Drug Interactions • Drug effects produced by • Modification of an expected drug response due to exposure to 1. Drug-receptor interaction© Jones & Bartlett Learning, LLC another drug or substance at approximately© Jones &the Bartlett same time; may Learning, be LLC 2. Drug-enzyme interactionNOT FOR SALE OR DISTRIBUTIONpharmacokinetic or pharmacodynamicNOT FOR SALE OR DISTRIBUTION 3. Nonspecific drug interaction • Pharmacokinetic—inhibition of absorption, enzyme inhibition, or induction that increases risk for drug toxicity or results in reduced • Drug receptors—cellular protein, enzyme, or membrane that, when drug effect, altered renal elimination bound to a drug, initiates a physiologic response or blocks a response • Pharmacodynamic—additive if two drugs have similar that© receptor Jones normally & Bartlett stimulates Learning, LLC © Jones & Bartlett Learning, LLC 1. Agonist—drug combines with receptor to stimulate a response pharmacodynamic effects, antagonistic if two drugs have opposing NOT FOR SALE OR DISTRIBUTION pharmacodynamicsNOT FOR effects SALE OR DISTRIBUTION 2. Antagonist—drug interferes with receptor action or with other drug agonists present • Drug–food interactions may decrease bioavailability by interfering with absorption; they may increase bioavailability via inhibition of • Drug–response relationship—study of relationship between enzymatic activity in intestinal wall concentration of drug in circulation and response obtained • Drug–herb interactions may decrease or increase bioavailability © Jones &1. Bartlett Affinity—propensity Learning, of a drug LLC to bind itself to a given receptor© site Jones & Bartlett Learning, LLC of drug NOT FOR SALE2. Efficacy—ability OR DISTRIBUTION to initiate biologic activity as a result of such NOT FOR SALE OR DISTRIBUTION binding • Therapeutic effect Drug Contraindications 1. All pharmacologic responses have a maximum effect at which no further response is achieved,© Jones regardless & Bartlettof drug concentration Learning, LLC• Allergies, medical conditions,© concurrent Jones use & of Bartlett another drug, Learning, age, LLC 2. Therapeutic range (window)—plasmaNOT FOR SALE concentration OR of DISTRIBUTION drug that pregnancy, lactation may be drugNOT contraindications FOR SALE OR DISTRIBUTION produces desired action without toxic effects • FDA Pregnancy and Lactation Labeling Rule (PLLR) (Food and Drug 3. Therapeutic index (TI)—ratio of lethal doses in 50% of population Administration, 2014) over the median minimum effective dose in 50% of the population; 1. Assists in assessing benefits versus risks of a drug for pregnant higher TI = safer drug women and nursing mothers © Jones & Bartlett Learning, LLC 2. Includes© Jonessubsections & for Bartlett pregnancy, lactation, Learning, and females LLC and males NOT FOR SALE OR DISTRIBUTION of reproductiveNOT FOR potential SALE in the Use OR in SpecialDISTRIBUTION Populations section. Adverse Reactions—Unintended, 3. Pregnancy letter categories