RESMRATE‘QDDEW GARE
`@[HIARDVQA@©E@@Y
`
`Joseph L. Ram, Ir. PhD, RRT
`Professor and Chair
`
`Cardiopulmonary Care Sciences
`College of Health and l-luman ScienCes
`Georgia State University
`Atlanta, Georgia
`
`SIXTH EDITION
`
`with 230 illustrations
`
`WA Mosby
`London
`Philadelphia
`Sydney Toronto
`
`St. Louis
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`Page 1 of 26
`
`

`

`N/J Mosby
`
`Acquisitions Editor: Karen Fabiano
`Developmental Editor: Mindy Copeland
`Project Manager: John Rogers
`Project Specialist: Beth Hayes
`Designer: Kathi Gosche
`Cover illustrator: Christine Oleksyk Perchal
`
`SIXTH EDI'I‘JUN
`
`Copyright ‘53 2002 by Mosby, Inc.
`
`Previous editions copyrighted 19?8, 1984, 1989. 1994. 1998.
`
`All rights reserved. No part oftliis publication maybe reproduced or transmitted in any Form orby
`any means, electronic or mechanical, Including photocopy, recording, or any information storage
`and retrieval system, without permission in writing From the publisher.
`
`NOTICE
`
`Pharmacology is an ever—changing field. Standard safety precautions must be followed, but as new
`research and clinical experience broaden our knowledge, changes in treatment and drug therapy may
`become necessary or appropriate. Readers are advised to check the most current product information
`provided by the manufacturer ofeach drug to be administered lo verify [he recommended dose, the
`method and duration of administration, and contraindications. It is the responsibility oithe treating
`physician, relying on experience and knowledge ofthe patient, to determine dosages and the best
`treatment for each individual patient. Neither the publisher nor the editor assumes any liability for
`any injury antifor damage to persons or property arising from this publication.
`
`Permission to photocopy or reproduce solely for internal or personal use is permitted for libraries or
`other users registered with the Copyright Clearance Center, provided that the base fee of $4 .00 per
`chapter plus $. IU per page is paid directly to the Copyright Clearance Center, 222 Rosewood Drive,
`Danvers, Massachusetts 01923. This consent does not extend to other kinds orcopying, such as
`copying for general distribution, for advertising or promotional purposes, for creating new collected
`works, or for resale.
`
`Mosby
`11830 Westlirte Industrial Drive
`St. Louis, MO 53146
`
`Printed in the United States ofAmerira
`
`Library of Congress Cataloging in Publication Data
`
`Rau, loseph L.
`Respiratory care pharmacology} Joseph L. Rau, lr.—61h ed.
`p. : cm.
`
`includes bibliographical references and index.
`ISBN [1—323—01696—0
`
`1. Respiratory agents. 2. Respiratory therapy. l,'l‘itle.
`IDNLM: 1. Itespiratory'l'herapy, 2. ltmnchodilator Agents—administration £1 dosage.
`3. Ilronchodilator Agents—pharmacology. Wit 342 112391“ 2002]
`RM338 12383 2002
`
`Gifi.2'0il46]—tlc2l
`
`2001052104
`
`02
`
`03
`
`04
`
`05
`
`06 TCXRRD-W 9
`
`8
`
`7
`
`6
`
`5
`
`4
`
`3 21
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-O1622
`
`Page 2 of 26
`
`

`

`
`
`Woman ._-.;
`
`Pharmacolrinetics oi inhaled aerosol drugs
`The Pharmacoclynamic Phase
`Structure-activity relations
`Nature and type of drug receptors
`Dose-response relations
`Phannacogenetics
`
`The Drug Administration Phase
`Drug dosage forms
`Routes of administration
`The Pharmacohinetic Phase
`
`Absorption
`Distribution
`Metabolism
`
`I Immuldmkwmw MW Mlmnruscode] ‘
`
`T he entire course of a drug’s action, from dose to
`effect, can be understood in three phases ofac-
`tion: the drug administration phase, the pharmacoiainetic
`phase, and the pharmacodynamic phase. This useful
`conceptual framework, based on the principles of-
`fered by Ariéns and Simonis,I organizes the steps ofa
`drug’s action from drug administration through effect
`and ultimate elimination from the body. This frame-
`work is illustrated in Figure SH, and provides an
`overview of the interrelationship of the three phases
`ofdrug action, each of which is discussed.
`
`
`THE Dnuo Annmlsrrtayou Pans:
`Definition: The drug artririm'stratien phase describes the
`method by which a drug dose is tirade available to the
`body.
`
`Dnuc DOSAGE Foams
`
`The drug administration phase entails the interrelated
`concepts ofdrug Formulation {e.g., compounding a
`tablet for particular dissolution properties] and drug
`delivery [e.g., designing an inhaler to deliver a unit
`dose). Two key topics of this phase are the drug
`dosage form and the route of administration. The
`drug dosageforin is the physical state ofthe drug in as-
`sociation with nondrug components such as the ve—
`hicle. 'I‘ablets, capsules, and injectable solutions are
`common examples ofdrug dosage forms. The more of
`rtdritinistmtiort is the portal of entry for the drug into
`12
`
`the body, such as oral [enteral], injection, or inhala-
`tion. The form in which a drug is available must be
`compatible with the route of administration desired.
`For example, the injectable route, such as intra-
`venously, requires a liquid solution ofa drug, whereas
`the oral route is possible with capsules, tablets, or liq-
`uid solutions. Some common drug formulations are
`listed in Box 2-] for each of the comtnon routes or
`drug administration.
`
`DRUG FURMHIAHONS {IND ADUI'J‘TW-Zfi‘
`
`A drug is the active ingredient in a dose formulation,
`but it is usually not the only ingredient in the total
`formulation. For example, in a capsule of an antibi-
`otic, the capsule itself is a gelatinous material that al-
`lows the drug to be swallowed. The capsule material
`then disintegrates in the stomach, and the active drug
`ingredient is released for absorption. The rate at
`which active drug is liberated from a capsule or tablet
`can be controlled during the formulation process, for
`example, by altering drug particle size or using a spe-
`cialized coating or formulation matrix. Aerosolixed
`agents for inhalation and treatment ofthe respiratory
`tract also contain ingredients other than the active
`drug. These include preservatives, propellants for me—
`tered dose inhaler formulations [MDIs], dispersants
`(surfactants), and carrier agents with dry powder in-
`halers (DPIs). An example ofthree formulations with
`differing ingredients for the adrenergic bronchodila—
`tor albuterol is given in Table 2- l. [n the nebulizer so-
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`Page 3 of 26
`
`

`

`lution, the benzalkonium chloride is a preservative
`and sulfuric acid adjusts the pH ofthe solution. in the
`MD], the chlorofluorocarbons are propellants and
`oleic acid is a dispersing agent. Similarly, in the DP]
`formulation, the lactose acts as a bulldog agent to im—
`prove uniform dispersion of the drug powder.
`
`ROUTES or ADMINISTRATION
`
`Advances in drug formulation and delivery systems
`have yielded a wide range of routes by a which a drug
`can be administered. In the discussion below, routes
`of administration have been divided into five broad
`
`categories: enteral, parenteral, inhalation,
`and topical.
`
`transdet‘mal,
`
`EN'I'HMI.
`
`The term entet‘ai refers literally to the small intestine,
`but the enteral route of administration is more
`broadly applicable to administration of drugs in—
`tended for absorption anywhere along the gastroin-
`testinal tract. The most common enteral route is by
`mouth (oral) because it is convenient, is painless, and
`offers flexibility in pOSsible dose forms ofthe drug, as
`seen Table 2—1.'The oral route requires the patient to
`be able to swallow, and airway protective reflexes
`should be intact. If the drug is not destroyed or inac-
`tivated in the stomach and can be absorbed into the
`
`bloodstream, distribution throughout the body and a
`
`PRINCIPLES OF DRUG ACTION
`
`13
`
`Phases of drug action:
`Dose to effect
`
`Drug administration—dose
`
`Dosage form
`Route of administration
`
`Pharmacokinetic phase
`I
`Absorption
`Distribution
`Metabolism
`Elimination
`
`Clearance
`
`Pharmacodynamic phase
`Y
`Drug + receptor
`I
`I. Metabolism.
`EFFECT
`E'lmmuon
`(stimulation, inhibition, etc.)
`Figure 2—1
`The conceptual scheme illustrating the major
`phases of dmg action in sequence, from dose administra—
`tion to effect in the body. {Modified from Ariéns E]. Simo-
`nis AM: Drug action: target tissue, dose-response relation-
`ships, and receptors. in Teorell T, Dedrick RL, Condliffe PC,
`eds: Pharmacology and pharnmcolcinetics. New York, 1974,
`Plenum Press.)
`
`Aerosol Trantdermal
`
`Patch
`Paste
`
`Topical
`Powder
`Lotion
`Ointment
`Solution
`
`893%] I Common Drug Formulations for Different Routes of Administration
`Enteral
`Parenteral
`Inhalation
`Tablet
`Solution
`Gas
`
`Capsule
`Suppository
`Elixir
`
`Suspension
`Depot
`
`
`Suspension
`
`Table 2-1
`
`
`
`Three different dosage forms for the bronchodilator drug albuterol indicating ingredients other
`than active drug
`
`IIWHE!
`
`Nebulizer solution
`Metered dose inhaler
`
`ltenzalltonium chloride, sulfuric acid
`'l‘richloromonofluoromethane, dichlorodiiluoromethane.
`oleic acid
`Lactose
`Albuterol
`Dry powder inhaler
`
`Albuterol sulfate
`Albuterol
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017-01622
`
`Page 4 of 26
`
`

`

`333% Device: for Inhaled Administration
`"
`'
`'
`of Drugs
`
`Ultrasonic nebulizer (USN)
`
`Vaporizer (anesthetic gases)
`Atom izer
`
`Nebulizer, small or large
`Metered dose inhaler [MDI), withfwithout spacer
`Dry powder inhaler (DPI)
`
`"I
`
`Basic Concepts and Principles in Pharmacology
`
`systemic effect can be achieved. Other enteral routes
`of administration include suppositories inserted in
`the rectum, tablets placed under the tongue (sublin-
`gual), and drug solutions introduced though an in-
`dwelling gastric tube.
`
`Paasnrram, {luminance}
`
`Technically, the term parenteral means ”besides the in—
`testine,” which implies any route of administration
`other than enteral. However, the parenteral route is
`commonly taken to mean injection ofa drug. Various
`options are available for injection ofa drug, the most
`common of which are the following:
`
`Intravenous (IV): Injected directly into the vein, al-
`lowing nearly instantaneous access to the systemic cir—
`culation. Drugs can be given as a bolus, in which case
`the entire dose is given rapidly, leading to a sharp rise
`in the plasma concentration, or a steady infusion can
`be used to avoid this precipitous rise.
`Intramuscular (IM): Injected deep into a skeletal
`muscle. Because the drug must be absorbed from the
`muscle into the systemic circulation, the drug effects
`occur more gradually than with intravenous injection,
`although typically more rapidly than by the oral route.
`Subcutaneous (SC): Injected into the subcutaneous
`tissue beneath the epidermis and dermis.
`
`Tnansoenamt.
`
`An increasing number of drugs are being formulated
`for application to the skin to produce a systemic ef-
`fect. The advantage of this route is that it can supply
`long—term continuous delivery to the systemic circu-
`lation. The drug is absorbed percutaneously, obviat-
`ing the need for a hypodermic needle and decreasing
`the fluctuations in plasma drug levels that can occur
`with repeated oral administration.
`
`Innam’non
`
`Drugs can be given by inhalation for either a systemic
`effect or a local effect in the lung. Two of the most
`common drug formulations given by this route are
`gases, which usually are given by inhalation for anes—
`thesia [a systemic effect), and aerosolized agents in-
`tended to target the lung or respiratory tract in the
`treatment of respiratory disease {local effect). The
`technology and science of aerosol drug delivery to
`the respiratory tract continues to develop and is de-
`scribed in detail in Chapter 3. A summary of devices
`commonly used for inhaled aerosol drug delivery
`is given in Box 2-2. The general
`rationale for
`
`aerosolized drug delivery to the airways for treating
`respiratory disease is the local delivery ofthe drug to
`the target organ, with reduced or minimal body ex-
`posure to the drug and hopefully reduced prevalence
`or severity of possible side effects.
`
`Tomcar.
`
`Drugs can be applied directly to the skin or mucous
`membranes to produce a local effect. Such drugs are
`often formulated to minimize systemic absorption.
`Examples oftopical administration include the ap—
`plication of corticosteroid cream to an area ofcon-
`tact dermatitis (e.g., poison ivy), administration of
`an eye drop containing a B-adrenergic antagonist
`to control glaucoma, and instillation of nasal
`drops containing an a-adrenergic agonist to relieve
`congestion.
`
`
`THE PHARMACOKIHIETIC Pnasr
`
`Definition: The pliarinacobinetic phase of drug action de-
`scribes the time course and disposition of a drug in the
`body, based on its absorption, distribution, metabolism and
`elimination.
`
`Once presented to the body, as described in the
`drug administration phase, a drug crosses local
`anatomical barriers to varying extents depending on
`its chemical properties and the physiological milieu
`ofthe body compartment it occupies. For a systemic
`effect it is desirable for the drug to get into the blood-
`stream for distribution to the body; for a local effect
`this is not desirable and can lead to unwanted side ef-
`
`fects throughout the body. The four topics ofabsorp-
`tion, distribution, metabolism, and elimination de—
`scribe the factors influencing and determining the
`course ofa drug after it is introduced to the body. In
`essence, phartnacobinetics describes what the body
`does to a drug and pharmacodynamics describes what
`the drug does to the body.
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`Page 5 of 26
`
`

`

`PRINCIPLES or DRUG Acnon
`
`15
`
`Stomach
`(pH = 3.0)
`
`Lipid
`membrane
`@fi
`000,. O hOOO
`Aque_0_us gifiusion
`
`Plasma
`(pH = 7.4)
`
`WW
`
`Weak acid drug
`(becomes nonionized in
`acidic compartments)
`
`H*
`
`H*
`«H
`Weak base drug
`(becomes ionized in
`acidic compartments)
`
`
`
`
`ABSORPTION
`
`When given orally for a systemic effect, a pill must
`first dissolve to liberate the active ingredient. The free
`drug must then reach the epithelial lining of the
`stomach or intestine and traverse the lipid membrane
`barriers of the gastric and vascular cells before reach-
`ing the bloodstream for distribution into the body.
`The lining of the lower respiratory tract also presents
`barriers to drug absorption. This mucosal barrier con-
`sists ofthe following five identifiable elements:
`
`F‘H‘ENI‘JE‘
`
`Airway surface liquid
`Epithelial cells
`Basement membrane
`Interstitium
`
`Capillary vascular network
`
`After traversing these layers a drug can reach the
`smooth muscle or glands of the airway. The mecha—
`nisms by which drugs move across membrane barriers
`are briefly outlined and include aqueous diffusion,
`lipid diffusion, active or facilitated diffusion, and
`pinocytosis. In general a drug must be sufficiently
`water-soluble to reach a lipid (cell) membrane and
`sufficiently lipid-soluble to diffuse across the cell bar—
`rier. Figure 2—2 illustrates these basic mechanisms,
`which will be briefly discussed.
`
`Aqueous DtFi-‘HSION
`
`This method of absorption occurs in the aqueous
`compartments of the body, such as interstitial spaces
`or within a cell. Transport across epithelial linings is
`restricted because of small pore size; capillaries have
`larger pores allowing passage of most drug molecules.
`Diffusion is by a concentration gradient.
`
`Limo Drrr-‘usroar
`
`Lipid diffusion is an important mechanism for drug
`absorption because of the many epithelial mem-
`branes that must be crossed ifa drug is to distribute in
`the body and reach its target organ. Epithelial cells
`have lipid membranes, and a drug must be lipid—
`soluble to diffuse across such a membrane. Lipid—
`insoluble drugs tend to be ionized, or have positive and
`negative charges separated on the molecule (polar).
`
`Lipid insoluble: Ionized, polar, water-soluble drug
`Lipid soluble: Nonionized, nonpolar drug
`
`Many drugs are weak acids or weak bases, and the de-
`gree ofionization ofthese molecules is dependent on
`the pKa (the pH at which the drug is 50% ionized and
`50% nonionized), the ambient pH, and whether the
`
`Illustration of pathways by which drugs can
`Figure 2-2
`traverse lipid membranes and enter the circulation. A mem-
`brane separating an acidic (stomach) and a neutral com—
`partment (plasma) is shown to illustrate that only the non-
`ionized form ofweak acids or weak bases substantially cross
`these Iipophilic barriers.
`
`drug is a weak acid or base. The direction ofincreasing
`ionization is opposite for weak acids and weak bases,
`as ambient pI-l changes.
`
`Weak acid: Because an acid contributes protons
`(l-l‘L ions), the protonated form is neutral, or non-
`ionized.
`
`Drug
`ttetltral
`(protonatcd)
`
`(:3:
`
`Drug‘
`anion
`
`+
`
`l I +
`proton
`
`Weak base: Because a base accepts protons (I-I+ ions}:
`the unprotonated form is neutral, or nonionized.
`
`Drug+
`cation
`(protonatetl)
`
`<:=:>
`
`Drug
`neutral
`
`+
`
`II'
`proton
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR201T-01622
`
`Page 6 of 26
`
`

`

`16
`
`Basic Concepts and Principles in Pharmacology
`
`I The protonated weak acid is neutralized by the ad-
`dition of H+ ions in an acidic environment, is
`
`nonionized, and is lipid-soluble.
`'- The protonated weak base gains a charge by
`adding I-I+ ions in an acidic environment, is ion—
`ized, and is not lipid-soluble.
`
`Figure 2-2 conceptually illustrates the principle oflipid
`diffusion and absorption for weak acids and bases.
`Some drugs, such as ethanol, are neutral molecules
`and are always nonionized. They are well-absorbed
`into the bloodstream and across the blood—brain bar-
`
`rier. Other drugs, such as ipratropium bromide or
`d-[+)-tubocurarine, are quaternary amines, have no
`unshared electrons for reversible binding of I 1* ions,
`and are permanently positively charged. Ipratropium
`is not lipid soluble, and does not absorb and distrib—
`ute well from the mouth or the lung with oral inhala-
`tion. A secondary or tertiary amine, such as atropine,
`can give up its l-iJr ion, and become nonionized, in-
`creasing its absorption and distribution, and conse-
`quent side effects, in the body.
`
`CarerursarMmmrrm Trmnsrom'
`
`Special carrier molecules embedded in the membrane
`can tranSport some substances, such as amino acids,
`sogars, or naturally occurring peptides and the drugs
`that resemble these substances. In some instances a
`
`drug can compete with the endogenous substance
`normally transported by the carrier.
`
`Pinocrmsrs
`
`Pinocytosis describes the incorporation ofa substance
`into a cell by a process ofmembrane engulfment and
`transport of the substance to the cell interior in vesi-
`cles, thereby allowing translocation across a mem-
`brane barrier.
`
`[herons Ai-‘r-‘rrrrrmt; ABSORPTION
`
`The route of administration determines which barri-
`
`ers to absorption must be crossed by a drug. This can
`affect the time course ofthe drug’s time to onset and
`time to peak effect. Intravenous administration by—
`passes the need for absorption from the gastrointesti-
`nal tract seen with oral administration, generally gives
`a very rapid onset and peak effect, and provides 100%
`availability of the drug in the bloodstream. The term
`bioavailability is used to indicate the proportion of a
`drug that reaches the systemic circulation. For exam~
`ple, the bioavailability of oral morphine is 0.24 be-
`
`cause only about a quarter of the morphine ingested
`actually arrives in the systemic circulation. Bioavail-
`ability is influenced not only by absorption but also
`by inactivation caused by stomach acids and by meta-
`bolic degradation, which can occur before the drug
`reaches the main systemic compartment. Another im—
`portant variable governing absorption and bioavail-
`ability is blood flow to the site ofabsorption.
`
`DISTRIBUTION
`
`To be effective at its desired site of action, a drug must
`have a certain concentration. For example, an antibi-
`otic is investigated for its minimai inhibitory concentra-
`tion (MIC). Drug distribution is the process by which a
`drug is transported to its sites of action, elimination,
`and storage. When given intravenously, most drugs dis-
`tribute initially to organs that receive the most blood
`flow. After this brief initial distribution phase, subse-
`quent phases of distribution occur based on the prin-
`ciples ofdiffusion and transport just outlined, as well
`as the drug’s physical/chemical nature and ability to
`bind to plasma proteins. The initial distribution phase
`is clinically important for lipophilic anesthetics (ega
`propofol, thiopental) because they produce rapid onset
`of anesthesia as a function the high blood flow to the
`brain and their effects are quickly terminated during
`redistribution to other tissues. The binding ofdrugs to
`plasma proteins can also be clinically relevant in rare
`instances, such as when a large portion ofa drug is in—
`active because it is bound to piasma proteins but sub-
`sequently becomes displaced (and thus active] by a sec-
`ond drug that binds to the same proteins.
`The plasma concentration ofa drug is partially de-
`termined by the rate and extent ofabsorption versus
`the rate of elimination for a given dose amount. In
`addition, the volume in which the drug is distributed
`also determines the concentration achieved in
`
`plasma. Those compartments and their approximate
`volumes in a 70-kg adult are given in Table 2-2.
`
`Table 2-2
`
`
`
`Volumes (approximate) of major body
`compartments
`
` @fivfifllfiffi
`
`i‘ifllfliifitlfll}
`
`Vascular (blood)
`Intersititial fluid
`Intracellular fluid
`
`5
`10
`20
`
`14-25
`Fat {adipose tissue)
`
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`Page 7 of 26
`
`

`

`VOLUME 01" Dtst'ttmu'mm
`
`Suppose a certain drug that distributes exclusively in
`the plasma compartment
`is administered intra-
`venously. If a lO-mg bolus of the drug is given, and
`the volume of the patient’s plasma compartment is
`5 L, then (barring degradation or elimination) the
`concentration in the plasma would be 2 mg/L. In this
`simple example, the volume of distribution (VD) is the
`same as the volume of the plasma compartment. In
`practice, drug distribution is usually more complex
`and the actual tissue compartments occupied by the
`drug are not known. Nonetheless, volume of distri—
`bution describes a useful mathematical equation re-
`lating the total amount of drug in the body to the
`plasma concentration.
`
`Volume of distribution (VD) = Drug amount/plasma concentration
`
`EXAMPLE
`If 350 mg of theophylline results in a concentration in the plasma oi l0 mgfL
`{equivalent to ‘10 ugr’mL), then the volume of distribution is calculated as:
`
`v,, : 350 mgns mgl'L
`vD = 35 L
`
`The drug can be absorbed and distributed into
`sites other than the vascular compartment, which is
`only approximately 5 L, and therefore the calculated
`volume of distribution can be much larger than the
`blood volume, as in the case of theophylline, which
`has a VD of 35 L. For this reason the volume of dis-
`tribution is referred to as the apparent volume of dis-
`tribution to emphasize that VD does not necessarily
`refer to an actual physiological space. In fact, drugs
`such as fluoxetine (an antidepressant) and inhaled
`anesthetics are sequestered in peripheral tissues, and
`therefore can have apparent volumes of distribution
`many times greater than the entire volume of the
`body.
`In a clinical setting, VD is rarely measured but is
`nonetheless important for estimating the dose needed
`for a given therapeutic level ofdrug. Itearranging the
`equation for VD, the drug amount should equal the
`VD multiplied by the concentration.
`
`EXAMPLE
`
`To achieve a concentration oi theophylline of 15 mst with a VD oi 35 L we
`calculate a dose of
`
`Drug amount (drug dose) = Plasma concentration X VD
`Dose = 15 trig/L X 35 I.
`Dose = 525 mg
`
`PRINCIPLES or DRUG Acnou
`
`17
`
`Several points should be noted. First, the above cal-
`culation assumes that the dose is completely available
`to the body. This may be true ifa dose is given intr‘ -
`venously, but there may be less than 100% bioavail-
`ability if given orally. Second, this is a loading dose, and
`subsequent doses to maintain a level ofconcentration
`will depend on the rate of absorption versus the rates
`of metabolism and excretion, to be discussed next.
`
`Third, the volume of distribution may change as
`a function of age or disease state. Fourth, the concept
`of the volume of distribution is not directly helpful
`in topical drug administration and delivery of
`aerosolized drugs intended to act directly on the air-
`way surface. The volume of distribution for topical
`deposition in the airway is not measured, and the
`drug is deposited locally in the respiratory tract, with
`some drugs absorbed from the airway into the blood.
`
`METABOLISM
`
`The processes by which drug molecules are metabo-
`lized, or biotransformed, constitutes a complex area
`of biochemistry, which is beyond the scope of this
`text. Common pathways for the biotransformation
`of drugs are listed in Box 2-3. Generally, phase 1
`biochemical reactions convert the active drug to a
`more polar [water-soluble) form, which can be ex-
`creted by the kidney. Drugs that are transformed in a
`phase 1 reaction also may be further transformed in
`a phase 2 reaction, which combines (conjugates) a
`substance (e.g., glucuronic acid) with the metabo-
`lite to form a highly polar conjugate. For some
`drugs, biotransformation is accomplished by just
`phase 1 or phase 2 metabolism without prior trans—
`formation by the other phase. Metabolites are often
`less biologically active than the parent drug. Never—
`theless, some drugs are inactive until metabolized
`
`853%) Common Pathway: for Drug Metabolism
`PhaseI
`
`Oxidative hydroxylation
`Oxidative dealkylation
`Oxidative deamination
`N-Oxidation
`Reductive reactions
`
`Conjugation reactions {e.g., glucuronide or sulfate)
`
`Hydrolytic reactions [e.g., esterase enzymes)
`
`Phase 2
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`Page 8 of 26
`
`

`

`13
`
`Basic Concepts and Principles in Pharmacology
`
`(e.g., enalapril) or produce metabolites that are
`more toxic than their progenitors (e.g., breakdown
`products of acetaminophen).
`
`Sm; 01-" Dane Bionmarsroiumnrw
`
`The liver is the principal organ for drug metabolism,
`although other tissues, including the lung, intestinal
`wall, and endothelial vascular wall, can transform or
`metabolize drugs. For example, epinephrine, a weak
`base, will be absorbed into the intestinal wall, where
`sulfatase enzymes inactivate it as the drug diffuses
`into the circulation. The liver contains intracellu-
`lar enzymes that usually convert lipophilic (lipid-
`soluble) drug molecules into waterwsoluble metabo—
`lites that are more easily excreted. The maior enzyme
`system in the liver is the cytochrome P450 oxidase
`system. There are many forms ofcytochrorne P450,
`which are hemoproteins with considerable substrate
`versatility and the ability to metabolize new drugs or
`industrial compounds. The various forms of cy-
`tochrome P450 have been divided into about a dozen
`subcategories, termed isoenzyme families. The four
`most important isoenzyme families for drug metab-
`olism have been designated CYPl, CYP2, CYPS, and
`CYP4. A given drug may be metabolized predomi—
`nately by only one member of an isoenzyme family.
`whereas another drug may be metabolized by multi-
`ple enzymes in the same family or even several dis-
`tinct enzymes across families. Knowing which partic-
`ular CYP enzyme(s) metabolizes a drug can be
`important for predicting drug interactions, as de-
`scribed further below.
`
`ENZYME INDUCTION AND INHIBITION
`
`Chronic administration or abuse ofdrugs that are me-
`tabolized by the enzyme systems in the liver can in
`duce (increase) or inhibit the levels of the enzymes
`[enzyme induction and inhibition). Some examples
`of drugs or agents that can induce or inhibit CYP en-
`zymes are listed in Table 2-3.
`Enzyme induction can affect the therapeutic doses
`of drugs required. For example, rifampin can induce
`CYI’ enzymes and increase the metabolism ofseveral
`drugs, including warfarin and oral contraceptives.
`Likewise, cigarette smoking can increase the break-
`down oftheophylline in chronic lung patients, caus-
`ing a shorter halflife ofthe drug from approximately
`7.0 hours to 4.3 hours. Dosages would need to be ad-
`justed accordingly to maintain a suitable plasma level
`of theophylline. Conversely, a substantial portion
`
`Table 2-3
`
`Drugs causing induction or inhibition of
`cytochrome P [CYP] enzymes
`
` $3i§iiiflzn -. marinas _ m.
`
`CYP1A2
`
`CYP2DG
`
`CYP3A4
`
`Phenytoin
`Rifampin
`
`Ciprofloxacin
`Diltiazem
`Ranitidine
`l-‘luoxetine
`
`Carbamazepine
`Corticosteroids
`
`Diltiazem
`Fluoxetine
`
`
`
`Rifampin Erythromycin
`
`of drug interactions involve inhibition of CYP en-
`zymes. A given drug is not likely to inhibit all the
`CYP isoenzymes equally. For example, the antibiotic
`ciprofloxacin is a potent inhibitor ofan enzyme in the
`CYP family, which also metabolizes theophylline.
`Thus coadministration of ciprofloxacin with the-
`ophylline can raise theophylline levels, the opposite
`effect ofcigarette smoking.
`
`FHH‘FPASS Ei’I-‘EG’I‘
`
`Another clinically important effect ofthe liver on drug
`metabolism is referred to as the first-pass effect of elim-
`ination. When a drug is taken orally and absorbed
`into the blood from the stomach or intestine, the por-
`tal vein drains this blood directly into the liver. This is
`illustrated in Figure 2-3. The blood from the liver is
`then drained by the right and left hepatic veins di—
`rectly into the inferior vena cava and on into the gen-
`eral circulation.
`
`If a drug is highly metabolized by the liver en-
`zymes briefly described and is administered orally,
`most of the drug’s activity will be terminated in its
`passage through the liver before it ever reaches the
`general circulation and the rest of the body. This is
`the first-pass effect. Examples of drugs with a high
`first-pass effect are propranolol, nitroglycerin (sub-
`lingual is preferred to oral), and fluticasone propi-
`onate, an aerosolized corticosteroid. The first-pass ef-
`fect causes difficulties with oral administration that
`
`must be overcome by increasing the oral dose [com—
`pared with the parenteral dosage) or by using a de-
`livery system that circumvents first-pass metabolism.
`The following routes avoid first-pass circulation
`through the liver: injection, buccal or sublingual
`tablets, the transdermal (e.g., patch) or rectal (e.g.,
`suppositories) route, and the inhalation route. These
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`Page 9 of 26
`
`

`

`PRINCIPLES or DRUG ACTION
`
`19
`
`To general
`circulation
`
`Inferior
`
`Esophageal It.
`
`
`Esophagus
`
`Drug
`
`Left gastric v.
`
`Liver
`
`
`
`
`Splenic v.
`
`I ”Pancreas
`
`Right gastroepiploic v.
`
`
`Gallbladder
`
`
`:7:-
`Colon
` ,_...--‘
`____..--
`{ascending}
`
`Colon
`(descending)
`
`Figure 2-3
`Anatomy ofvenous drainage from the stomach that forms the basis for the first—
`pass effect of orally administered drugs.
`
`routes of administration bypass the liver’s portal ve-
`nous circulation, allowing drugs to be generally dis-
`tributed in the body before being circulated through
`the liver and ultimately metabolized. They also by-
`pass metabolic degradation occurring in the gut as a
`result of specific metabolic enzymes [e.g., CYP3) or
`bacterial flora.
`
`ELIMINATION
`
`The primary site of drug excretion in the body is the
`kidney, just as the liver is the site ofrnuch drug me-
`tabolism. The kidney is important for removing drug
`metabolites produced by the liver. Some drugs are
`not metabolized and are eliminated from the circu-
`
`lation entirely by the kidney. The route of elimina-
`tion becomes important when choosing between al-
`ternative therapies, because liver or kidney disease
`can alter the clearance of a drug by these organs. In
`
`general terms, clearance is a measure of the body's
`ability to rid itself ofa drug. Most often, clearance is
`expressed as total systemic or plasma clearance to em-
`phasize that ail of the various mechanisms by which
`a given drug is cleared (metabolism, excretion, etc.)
`are taken into account.
`
`PMSMA Grammars;
`
`Just as the term VD is an abstraction that does not
`usually correspond to any real physiological volume,
`so the term plasma clearance [Clp) refers to a hypo-
`thetical volume of plasma that is completely cleared
`of all drug over a given period. Consequently.
`plasma clearance is usually expressed as liters per
`hour (L/hr), or ifbody weight is taken into account,
`liters per hour per kilogram. Because Cll, gives an in-
`dication of the quantity of drug removed from the
`body over a given time, it can be used to estimate the
`
`UNITED THERAPEUTICS, EX. 2047
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017-01622
`
`Page 10 of 26
`
`

`

`20
`
`Basic Concepts and Principles in Pharmacology
`
`rate at which drug must be replaced to maintain a
`steady plasma level.
`
`MAINTENANCE Dose
`
`Plasma
`drug
`"WEI
`
`Factors shaping curve:
`Flate of absorption. close
`Distribution
`
`Clearance
`
`
`
`Metabolism rate
`
`Elimination rats-
`
`
`To achieve a steady level of drug in the body, dosing
`must equal the rate of eliminat