RS awe)
`edition
`
`Basic &Clinical
`
`Bertram G. Katzung
`
`Pharmacology
`
`I .
`I
`
`i.
`
` DRL - EXHIBIT 1025
`
`

`

`

`

`Basic & Clinical
`Pharmacology
`
`

`

`

`

`

`

`Drug Receptors &
`Pharmacodynamics
`
`Henry R. Bourne, MD, & James M. Roberts, MD
`
`2
`
`The therapeutic and toxic effects of drugs result from
`their interactions with molecules in the patient. In
`most instances, drugs act by associating with specific
`macromolecules in ways that alter their biochemical or
`biophysical activity. This idea, now almost a century
`old, is embodied in the terms receptive substance and
`receptor: the component of a cell or organism that in(cid:173)
`teracts with a drug and initiates the chain of biochemi(cid:173)
`cal events leading to the drug's observed effects.
`Initially, the existence of receptors was inferred
`from observations of the chemical and physiologic
`specificity of drug effects. Thus, Ehrlich noted that
`certain synthetic organic agents had characteristic an(cid:173)
`tiparasitic effects while other agents did not, though
`their chemical structures differed only slightly.
`Langley noted that curare did not prevent electrical
`stimulation of muscle contraction but did block con(cid:173)
`traction triggered by nicotine. From these simple be(cid:173)
`ginnings, receptors have now become the central fo(cid:173)
`cus of investigation of drug effects and
`their
`mechanisms of action (pharmacodynamics). There(cid:173)
`ceptor concept, extended to endocrinology, immunol(cid:173)
`ogy, and molecular biology, has proved essential for
`explaining many aspects of biologic regulation. Drug
`receptors are now being isolated and characterized as
`macromolecules, thus opening the way to precise un(cid:173)
`derstanding of the molecular basis of drug action.
`In addition to its usefulness for explaining biology,
`the receptor concept has immensely important practi(cid:173)
`cal consequences for the development of drugs and
`for making therapeutic decisions in clinical practice.
`These consequences-explained more fully in later
`sections of this chapter-form the basis for under(cid:173)
`standing the actions and clinical uses of drugs de(cid:173)
`scribed in every chapter of this book. They may be
`briefly summarized as follows:
`{1} Receptors largely determine the quantita=
`Uve reijations between dose or comcentration of
`dmg and pharmacologic effects. The receptor's
`affinity for binding a drug determines the concentra(cid:173)
`tion of drug required to form a significant number of
`drug-receptor complexes, and the total number of re(cid:173)
`ceptors often limits the maximal effect a drug may
`produce.
`{2) Receptors are responsible for se~ectlvUy
`
`of drug action. The molecular size, shape, and elec(cid:173)
`trical charge of a drug determine whether~and with
`what avidity-it will bind to a particular receptor
`among the vast array of chemically different binding
`sites available in a cell, animal, or patient. Accord(cid:173)
`ingly, changes in the chemical structure of a drug can
`dramatically increase or decrease a new drug's affini(cid:173)
`ties for different classes of receptors, with resulting
`alterations in therapeutic and toxic effects.
`(3) Receptors mediate the actions of phar(cid:173)
`macologic antagonists. Many drugs and endo(cid:173)
`genous chemical signals, such as hormones, regulate
`the function of receptor macromolecules as agonists;
`ie, they change the function of a macromolecule as a
`more or less direct result of binding to it. Pure phar(cid:173)
`macologic antagonists, however, bind to receptors
`without directly altering the receptors' function.
`Thus, the effect of a pure antagonist on a cell or in a
`patient depends entirely upon its preventing the bind(cid:173)
`ing of agonist molecules and blocking their biologic
`actions. Some of the most useful drugs in clinical
`medicine are pharmacologic antagonists.
`
`MACROMOLECULAR NATURE
`OF DRUG RECEPTORS
`
`Until recently, the chemical structures and even the
`existence of receptors for most drugs could only be
`inferred from the chemical structures of the drugs
`themselves. Now, however, receptors for many drugs
`have been biochemically purified and characterized.
`The accompanying box describes some of the methods
`by which receptors are discovered and defined. Most
`receptors are proteins, presumably because the struc(cid:173)
`tures of polypeptides provide both the necessary di(cid:173)
`versity and the necessary specificity of shape and
`electrical charge.
`The best-characterized drug receptors are regula(cid:173)
`tory proteins, which mediate the actions of endo(cid:173)
`genous chemical signals such as neurotransmitters,
`autacoids, and hormones. This class of receptors me(cid:173)
`diates the effects of many of the most useful thera(cid:173)
`peutic agents. The molecular structures and bio(cid:173)
`chemical mechanisms of these regulatory receptors
`
`9
`
`

`

`10 I CHAPTER 2
`
`HOW ARE RECEPTORS DISCOVERED?
`
`Because today's new receptor sets the stage for
`tomorrow' s new drug, it is important to know how
`new receptors are discovered. The discovery proc(cid:173)
`ess follows a few key steps, summarized in Figure
`2-1. As presented in greater detail elsewhere in
`this chapter, the process of defining a new receptor
`(stage 1 in Figure 2-1) begins by studying there(cid:173)
`lations between structures and activities of a group
`of drugs on some conveniently measured re(cid:173)
`sponse. Binding of radioactive ligands defines the
`molar abundance and binding affinities of the pu(cid:173)
`tative receptor and provides an assay to aid in its
`biochemical purification. Analysis of the pure re(cid:173)
`ceptor protein tells us the number of its subunits,
`its size, and (sometimes) provides a clue to how it
`works (eg, agonist-stimulated autophosphoryla(cid:173)
`tion on tyrosine residues, seen with receptors for
`insulin and many growth factors).
`These "classic" steps in receptor identification
`now serve as a warming-up exercise for a power(cid:173)
`ful new experimental strategy aimed at molecular
`cloning of the segment of DNA that encodes the
`receptor (stages 2-5 in Figure 2- 1). The core of
`this strategy is the ability to identify a putative re(cid:173)
`ceptor DNA sequence in a representative popula(cid:173)
`tion of cDNAs (DNA sequences complementary
`to the messenger RNAs expressed in an appropri(cid:173)
`ate cell or tissue are obtained by means of reverse
`transcriptase). To do so (stage 2), investigators use
`biochemical and functional features of the recep(cid:173)
`tor protein as handles for picking out the corre(cid:173)
`sponding DNA. Thus, an antibody raised against
`the pure receptor protein or nucleic acid sequences
`based on its amino acid sequence may distinguish
`a bacterial colony containing putative receptor
`eDNA
`from
`colonies
`containing
`irrelevant
`cDNAs, by binding to receptor antigen expressed
`in the bacterium (2a) or by hybridizing to receptor
`DNA (2b), respectively. Alternatively, the popula(cid:173)
`tion of cDNAs may be expressed as proteins in
`frog oocytes or vertebrate cells, and the putative
`receptor eDNA can then be detected by virtue of
`the protein's signaling function (2c) or its ability
`to bind a specific ligand (2d).
`Once the putative receptor eDNA has been
`
`identified, it is "validated" by carefully comparing
`the function and biochemical properties of the re(cid:173)
`combinant protein with those of the endogenous
`receptor that originally triggered the search (3a).
`The base sequence of the receptor DNA is also de(cid:173)
`termined (3b ), so that the amino acid sequence of
`the complete receptor protein can be deduced and
`compared with sequences of known receptors. Based
`on these criteria, it may then be possible to announce
`the identification of a new receptor (step 4).
`A much greater quantity and quality of informa(cid:173)
`tion flows from molecular cloning of the eDNA
`encoding a new receptor than from identifying a
`receptor in the "classic" way. The deduced amino
`acid sequence almost always resembles those of
`previously known receptors. Investigators can im(cid:173)
`mediately place the new receptor into a specific
`class of known receptors, and the structural class
`tells us how the receptor works-whether it is a
`receptor tyrosine kinase, a seven-transmembrane
`region receptor coupled to G proteins, etc. The
`DNA sequence provides a probe to identify cells
`and tissues that express messenger RNA encoding
`the new receptor. Expression of the eDNA in cul(cid:173)
`tured cells gives the pharmaceutical chemist an
`unlimited supply of recombinant receptor protein
`for precise biochemical analysis, tests of agonist
`and antagonist binding, and development of new
`drugs.
`Finally (step 5), the receptor DNA itself pro(cid:173)
`vides a tool for identifying yet more receptors. Re(cid:173)
`ceptors within a specific class or subclass contain
`highly conserved regions of similar or identical
`amino acid (and therefore DNA) sequence. The
`DNA sequences corresponding to these conserved
`regions can be used as probes to find sequences of
`related but potentially novel receptors, either by
`DNA-DNA hybridization (2b) or as primers in a
`polymerase chain reaction (PCR) designed to am(cid:173)
`plify receptor DNA sequences (2e). These probes
`may lead to cloning DNA encoding a receptor
`whose ligand is unknown (an "orphan" receptor);
`the appropriate ligand is then sought by testing for
`functional and binding interactions with the re(cid:173)
`combinant receptor.
`
`are described in a later section entitled Signaling
`Mechanisms and Drug Action.
`Other classes of proteins that have been clearly
`identified as drug receptors include enzymes, which
`may be inhibited (or, less commonly, activated) by
`binding a drug (eg, dihydrofolate reductase, the re(cid:173)
`ceptor for the antineoplastic drug methotrexate);
`transport proteins (eg, Na+JK+ ATPase, the mem-
`
`brane receptor for cardioactive digitalis glycosides);
`and structural proteins (eg, tubulin, the receptor for
`colchicine, an anti-inflammatory agent).
`This chapter deals with three aspects of drug recep(cid:173)
`tor function, presented in increasing order of com(cid:173)
`plexity: (1) The first aspect is their function as deter(cid:173)
`minants of the quantitative relation between the
`concentration of a drug and the pharmacologic re-
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`tagonist produces no such change in receptor confor(cid:173)
`mation; in this view, the partial agonist changes re(cid:173)
`ceptor conformation, but not to the extent necessary
`to result in full activation of the occupied receptor.
`To express this idea, pharmacologists refer to the
`efficacy of a drug as a way of indicating the relation
`between occupancy of receptor sites and the pharma(cid:173)
`cologic response. A drug may have zero efficacy (ie,
`may be a pure antagonist) or any degree of efficacy
`greater than zero. Partial agonists can be viewed as
`drugs with such low efficacy that even occupancy of
`the full complement of receptors does not result in the
`maximal response that can be elicited by other
`("full") agonists, which have higher efficacy. The
`reader will see that many drugs used as competitive
`antagonists are in fact weak partial agonists.
`
`Other Mechanisms
`of Drug Antagonism
`Not all of the mechanisms of antagonism involve
`interactions of drugs or endogenous ligands at a sin(cid:173)
`gle type of receptor. Indeed, chemical antagonists
`need not involve a receptor at all. Thus, one drug may
`antagonize the actions of a second drug by binding to
`and inactivating the second drug. For example, pro(cid:173)
`tamine, a protein that is positively charged at physi(cid:173)
`ologic pH, can be used clinically to counteract the ef(cid:173)
`fects of heparin, an anticoagulant that is negatively
`charged; in this case, one drug antagonizes the other
`simply by binding it and making it unavailable for in(cid:173)
`teractions with proteins involved in formation of a
`blood clot.
`The clinician often uses drugs that take advantage
`of physiologic antagonism between endogenous
`regulatory pathways. Many physiologic functions are
`controlled by opposing regulatory pathways. For ex(cid:173)
`ample, several catabolic actions of the glucocorticoid
`hormones lead to increased blood sugar, an effect that
`is physiologically opposed by insulin. Although glu(cid:173)
`cocorticoids and insulin act on quite distinct receptor(cid:173)
`effector systems, the clinician must sometimes ad(cid:173)
`minister insulin to oppose the hyperglycemic effects
`of glucocorticoid hormone, whether the latter are ele(cid:173)
`vated by endogenous synthesis ( eg, a tumor of the ad(cid:173)
`renal cortex) or as a result of glucocorticoid therapy.
`In general, use of a drug as a physiologic antago(cid:173)
`nist produces effects that are less specific and less
`easy to control than are the effects of a receptor-spe(cid:173)
`cific antagonist. Thus, for example, to treat brady(cid:173)
`cardia caused by increased release of acetylcholine
`from vagus nerve endings, which may be caused by
`the pain of myocardial infarction, the physician could
`use isoproterenol, a beta-adrenoceptor agonist that in(cid:173)
`creases heart rate by mimicking sympathetic stimula(cid:173)
`tion of the heart. However, use of this physiologic an(cid:173)
`tagonist would be less rational-and potentially more
`dangerous-than would use of a receptor-specific an(cid:173)
`tagonist such as atropine (a competitive antagonist at
`the receptors at which acetylcholine slows heart rate).
`
`DRUG RECEPTORS & PHARMACODYNAMICS I 17
`
`SIGNALING MECHANISMS
`& DRUG ACTION
`,
`
`Until now we have considered receptor interac(cid:173)
`tions and drug effects in terms of equations and con(cid:173)
`centration-effect curves. This abstract analysis ex(cid:173)
`plains some quantitative aspects of drug action. For a
`more complete explanation, we must also understand
`the molecular mechanisms by which a drug acts. This
`understanding is particularly important for drugs that
`mimic or block intercellular signaling by hormones
`and neurotransmitters.
`The research of the past 10 years has revealed in
`considerable detail the molecular processes that
`transduce extracellular signals into intracellular mes(cid:173)
`sages that control cell function. Understanding these
`remarkable signaling mechanisms allows us to ask
`basic questions with important clinical implications:
`Why do some drugs produce effects that persist for
`minutes, hours, or even days after the drug is no
`longer present? How do cellular mechanisms for am(cid:173)
`plifying external chemical signals explain the phe(cid:173)
`nomenon of spare receptors? Why do chemically
`similar drugs often exhibit extraordinary selectivity
`in their actions? Can the signaling mechanisms ex(cid:173)
`plain actions of drugs that do not interact with recep(cid:173)
`tors? Do these mechanisms provide targets for devel(cid:173)
`oping new drugs? Our new understanding allows us
`not only to ask these questions but also-in many
`cases-
`to answer them.
`Most transmembrane signaling is accomplished by
`only a few different molecular mechanisms. Each
`type of mechanism has been adapted, through the
`evolution of distinctive protein families, to transduce
`many different signals. These protein families include
`receptors on the cell surface and within the cell, as
`well as enzymes and other components that generate,
`amplify, coordinate, and terminate postreceptor sig(cid:173)
`naling by chemical second messengers in the cyto(cid:173)
`plasm. This section first discusses the mechanisms
`for carrying chemical information across the plasma
`membrane, and then outlines key features of cyto(cid:173)
`plasmic second messengers.
`Four basic mechanisms of transmembrane signal(cid:173)
`ing are well understood (Figure 2- 7). Each uses a dif(cid:173)
`ferent strategy to circumvent the barrier posed by the
`lipid bilayer of the plasma membrane. These strate(cid:173)
`gies are (1) using a lipid-soluble ligand that crosses
`the membrane and acts on an intracellular receptor;
`(2) using a transmembrane receptor protein whose in(cid:173)
`tracellular enzymatic activity is allosterically regu(cid:173)
`lated by a ligand that binds to a site on the protein's
`extracellular domain; (3) using a ligand-gated trans(cid:173)
`membrane ion channel that can be induced to open or
`close by the binding of a ligand; and (4) using a trans(cid:173)
`membrane receptor protein to stimulate a GTP-bind(cid:173)
`ing signal transducer protein (G protein) that in turn
`generates an intracellular second messenger.
`Of course, the signaling mechanisms for many ex-
`
`

`

`

`

`

`

`

`

`

`

`22 I CHAPTER 2
`
`Table 2-2. G proteins and their receptors and effectors.
`
`G
`Protein
`
`Gs
`
`G;t, Gi2•
`G;3
`
`Golf
`
`Go
`
`Gq
`
`Gt1• Gt2
`
`Receptors for:
`13-Adrenergic
`amines, glucagon,
`histamtne,
`serotonin, and
`many other
`hormones
`
`~-Adrenergic
`amines,
`acetylcholine
`(muscarinic),
`opioids, serotonin,
`and many others
`Odorants (olfactory
`epithelium)
`Neurotransmitters
`in brain (not yet
`specifically
`identified)
`Acetylcholine (eg,
`muscarinic),
`bombesin ,
`serotonin (5-HT 1c;),
`and many others
`Photons (rhodopsin
`and color opsins in
`retinal rod and cone
`cells)
`
`Effector/Signaling
`Pathway
`IAdenylyl cyclase~
`I cAMP
`
`Several, including:
`JAdenylyl cyclase ~
`.J.cAMP
`Open cardiac K+
`channels --'>
`.!.heart rate
`I Adenylyl cyclase -->
`i cAMP
`Not yet clear
`
`! Phospholipase C --'>
`I IP3, diacylglycerol,
`cytoplasmic Ca2+
`
`lcGMP
`phosphodiesterase --'>
`.J.cGMP
`(phototransduction)
`
`I
`
`I
`
`I
`
`I
`
`I
`
`odorants, and even visual receptors (in retinal rod and
`cone cells) all belong to the serpentine family. The
`amino and carboxyl terminals of each of these recep(cid:173)
`tors are located on the extracellular and cytoplasmic
`sides of the membrane, respectively. Different ser(cid:173)
`pentine receptor~ resemble one another rather closely
`in amino acid sequences and in the locations of their
`hydrophobic transmembrane regions and hydrophilic
`extra- and intracellular loops, suggesting that all were
`derived from a common evolutionary precursor.
`In parallel with these structural similarities, it ap(cid:173)
`pears that serpentine receptors transduce signals
`across the plasma membrane in essentially the same
`way . Often the agonist ligand--eg, a catecholamine,
`acetylcholine, or the photon-activated chromophore
`of retinal photoreceptors-is bound in a pocket en(cid:173)
`closed by the transmembrane regions of the receptor
`(as in Figure 2- 12). The resulting change in confor(cid:173)
`mation of these regions is transmitted to cytoplasmic
`loops of the receptor, which in turn activate the ap(cid:173)
`propriate G protein by promoting replacement of
`GDP by GTP, as described above. Considerable bio(cid:173)
`chemical evidence indicates that the G proteins inter(cid:173)
`act with amino acids in the third cytoplasmic loop of
`the receptor polypeptide (arrowed in Figure 2-12).
`The carboxyl terminal tails of these receptors, also lo(cid:173)
`cated in the cytoplasm, can regulate the receptors'
`ability to interact with G proteins, as described below.
`
`Receptor Desensitization
`Receptor-mediated responses to drugs and hormo(cid:173)
`nal agonists often "desensitize" with time (Figure
`2- 13, top). After reaching an initial high level, there(cid:173)
`sponse (eg, cellular cAMP accumulation, Na+ influx,
`contractility, etc) gradually diminishes over seconds
`or minutes, even in the continued presence of the
`agonist. This desensitization is usually reversible.
`Thus, 15 minutes after removal of the agonist, a sec(cid:173)
`ond exposure to agonist results in a response similar
`to the initial response. (Note that this ready revers(cid:173)
`ibility distinguishes desensitization from down-regu(cid:173)
`lation of the number of receptors, as described above
`for receptor tyrosine kinases.)
`Although many kinds of receptors undergo desen(cid:173)
`sitization, the mechanism is in most cases obscure
`(eg, agonist-induced desensitization of the nicotinic
`acetylcholine receptor). The molecular mechanism of
`agonist desensitization has been worked out in some
`detail, however, in the case of the beta adrenoceptor
`(Figure 2-13, bottom): Binding of agonist induces a
`change in conformation of the receptor' s carboxyl
`terminal tail, making it a good substrate for phos(cid:173)
`phorylation on serine (and threonine) residues by a
`specific kinase, ~-adrenoceptor kinase (also termed
`~ARK). The presence of phosphoserines increases
`the receptor' s affinity for binding a third protein, ~­
`arrestin. Binding of ~ - arrestin to cytoplasmic loops of
`the receptor diminishes the receptor's ability to inter(cid:173)
`act with Gs, thereby reducing the agonist response (ie,
`stimulation of adenylyl cyclase). Upon removal of
`agonist, however, cellular phosphatases remove
`phosphates from the receptor and ~ARK stops putting
`them back on, so that the receptor- and consequently
`the agonist response-return to normal (Figure 2- 13,
`bottom).
`
`Well-Established Second
`Messengers
`A. cAMP: Acting as an intracellular second mes(cid:173)
`senger, cAMP mediates such hormonal responses as
`the mobilization of stored energy (the breakdown of
`carbohydrates in liver or triglycerides in fat cells
`stimulated by beta-adrenomimetic catecholamines),
`vasopressin-mediated conservation of water by the
`kidney, Ca2+ homeostasis (regulated by parathyroid
`hormone), and increased rate and contraction force of
`the heart muscle (beta-adrenomimetic catechola(cid:173)
`mines). It also regulates the production of adrenal and
`sex steroids (in response to corticotropin or follicle(cid:173)
`stimulating hormone), the relaxation of smooth mus(cid:173)
`cle, and many other endocrine and neural processes.
`cAMP exerts most of its effects by stimulating
`cAMP-dependent protein kinases (Figure 2-14).
`These tetrameric kinases are . composed of a cAMP(cid:173)
`binding regulatory (R) dimer and two catalytic (C)
`chains. When cAMP binds to the R dimer, active C
`chains are released, which then diffuse through the
`cytoplasm and nucleus, where they transfer phos-
`
`

`

`

`

`

`

`

`

`26 I CHAPTER 2
`
`Phosphorylation:
`A Common Theme
`Almost all second messenger signaling involves re(cid:173)
`versible phosphorylation. It plays a key role at every
`step, from regulation of receptors (autophosphoryla(cid:173)
`tion of tyrosine kinases and desensitization of recep(cid:173)
`tors linked to G proteins) to kinases regulated by sec(cid:173)
`ond messengers, and finally to substrates of these
`kinases that may themselves be kinases. These cova(cid:173)
`lent modifications perform two principal functions in
`signaling, amplification and flexible regulation. In
`amplification, rather like GTP bound to a G protein,
`the attachment of a phosphoryl group to a serine,
`threonine, or tyrosine residue powerfully amplifies
`the initial regulatory signal by recording a molecular
`memory that the pathway has been activated; dephos(cid:173)
`phorylation erases the memory, taking a longer time
`to do so than is required for dissociation of an allo(cid:173)
`steric ligand. In flexible regulation, differing sub(cid:173)
`strate specificities of the multiple protein kinases
`regulated by second messengers provide branch
`points in signaling pathways that may be inde(cid:173)
`pendently regulated. In this way, cAMP, Ca2+, or
`other second messengers can use the presence or ab(cid:173)
`sence of particular kinases or kinase substrates to pro(cid:173)
`duce quite different effects in different cell types.
`
`RECEPTOR CLASSES
`& DRUG DEVELOPMENT
`
`As we have seen, the existence of a specific drug
`receptor is usually inferred from studying the struc(cid:173)
`ture-activity relationship of a group of structurally
`similar congeners of the drug that mimic or antago(cid:173)
`nize its effects. Thus, if a series of related agonists
`exhibits identical relative potencies in producing two
`distinct effects, it is likely that the two effects are me(cid:173)
`diated by similar or identical receptor molecules. In
`addition, if identical receptors mediate both effects, a
`competitive antagonist will inhibit both responses
`with the same K1; a second competitive antagonist
`will inhibit both responses with its own characteristic
`K1• Thus, studies of the relation between structure and
`activity of a series of agonists and antagonists can
`identify a species of receptor that mediates a set of
`pharmacologic responses.
`Exactly the same experimental procedure can show
`that observed effects of a drug are mediated by differ(cid:173)
`ent receptors. In this case, effects mediated by differ(cid:173)
`ent receptors may exhibit different orders of potency
`among agonists, and different K1 values for each com(cid:173)
`petitive antagonist.
`Wherever we look, JJ?Ore than one class of receptor
`seems to have evolved for every chemical signal. For
`example, structure-activity studies with chemical
`congeners of acetylcholine, histamine, and catecho(cid:173)
`lamines have identified multiple receptors for each of
`these endogenous ligands. Ligand-binding and mo-
`
`lecular cloning techniques continue to reveal addi(cid:173)
`tional receptors eg, two classes of vasopressin recep(cid:173)
`tors, five molecular species of muscarinic receptors
`(only three of which are distinguishable by ligand(cid:173)
`binding techniques), and multiple classes of receptors
`for dopamine, opioid peptides, serotonin, and others.
`Why do multiple receptors for a single ligand ex(cid:173)
`ist? The answer is quite straightforward: Cells use
`more than one signaling pathway to respond to each
`endogenous ligand, and therefore need more than one
`receptor for the same ligand. Thus, acetylcholine uses
`a nicotinic AChR to initiate a fast excitatory postsy(cid:173)
`naptic potential (EPSP) in the postganglionic cells of
`autonomic ganglia and muscarinic receptors to evoke
`a slow EPSP, which modulates responsiveness to the
`fast EPSP in the same cells.
`The existence of multiple receptors for each endog(cid:173)
`enous signaling ligand creates many important oppor(cid:173)
`tunities for drug development. Although each en(cid:173)
`dogenous ligand produces multiple clinical effects, it
`is often therapeutically advantageous to block or
`mimic one set of effects without affecting the others.
`Subtle structural differences in the binding sites of
`two receptors for a ligand can make them bind conge(cid:173)
`ners of the ligand with different affinities. If the af(cid:173)
`finities are sufficiently different, it may be possible to
`develop a drug that acts selectively, producing its ef(cid:173)
`fects through one receptor and not the other. Thus, P(cid:173)
`adrenoceptor antagonists can block cardioaccelera(cid:173)
`tion produced by norepinephrine without preventing
`norepinephrine from constricting blood vessels via a 1
`adrenoceptors. Clinical uses of receptor-selective
`drugs are described in almost every chapter of this
`book.
`New drug development is not confined to agents
`that act on receptors for extracellular chemical sig(cid:173)
`nals. Pharmaceutical chemists are now determining
`whether elements of signaling pathways distal to the
`receptors may also serve as targets of selective and
`useful drugs. For example, clinically useful agents
`might be developed that act selectively on specific G
`proteins, kinases, phosphatases, or the enzymes that
`degrade second messengers.
`
`RELATION BETWEEN DRUG DOSE
`& CLINICAL RESPONSE
`
`We have dealt with receptors as molecules and
`shown how receptors can quantitatively account for
`the relation between dose or concentration of a drug
`and pharmacologic responses, at least in an idealized
`system. When faced with a patient who needs treat(cid:173)
`ment, the physician must make a choice among a va(cid:173)
`riety of possible drugs and devise a dosage regimen
`that is likely to produce maximal benefit and minimal
`toxicity. Because the patient is never an idealized sys(cid:173)
`tem, the physician will not have precise information
`about the physicochemical nature of the receptors in-
`
`

`

`

`

`

`

`T
`
`.....
`
`quanta! effect are 5 and 500 mg, respectively, then the
`first drug can be said to be 100 times more potent than
`the second for that particular effect. Similarly, one
`can obtain a valuable index of the selectivity of a
`drug's action by comparing its ED50s for two differ(cid:173)
`ent quanta] effects in a population (eg, cough sup(cid:173)
`pression versus sedation for opiate drugs; increase in
`heart rate versus increased vasoconstriction for sym(cid:173)
`pathomimetic amines; anti-inflammatory effects ver(cid:173)
`sus sodium retention for corticosteroids; etc).
`Quanta] dose-effect curves may also be used to
`generate information regarding the margin of safety
`to be expected from a particular drug used to produce
`a specified effect. One measure, which relates the
`dose of a drug required to produce a desired effect to
`that which produces an undesired effect, is the thera(cid:173)
`peutic index. In animal studies, the therapeutic index
`is usually defined as the ratio of the TD50 to the
`ED50 for some therapeutically relevant effect. The
`precision possible in animal experiments may make it
`useful to use such a therapeutic index to estimate the
`potential effectiveness of a drug in humans. Of
`course, the therapeutic index of a drug in humans is
`almost never known with real precision; instead, drug
`trials and accumulated clinical experience often re(cid:173)
`veal a range of usually effective doses and a different
`(but sometimes overlapping) range of possibly toxic
`doses. The clinically acceptable risk of toxicity de(cid:173)
`pends critically on the severity of the disease being
`treated. For example, the dose range that provides re(cid:173)
`lief from an ordinary headache in the great majority
`of patients should be very much lower than the dose
`range that produces serious toxicity, even if the toxic(cid:173)
`ity occurs in a small minority of patients. However,
`for treatment of a lethal disease such as Hodgkin's
`lymphoma, the acceptable difference between thera(cid:173)
`peutic and toxic doses may be smaller.
`Finally, note that the quanta] dose-effect curve and
`the graded dose-response curve summarize somewhat
`different sets of information, although both appear
`sigmoid in shape on a semilogarithmic plot (compare
`Figures 2-16 and 2-17). Critical information re(cid:173)
`quired for making rational therapeutic decisions can
`be obtained from each type of curve: Both curves pro(cid:173)
`vide information regarding the potency and selectiv(cid:173)
`ity of drugs; the graded dose-response curve indicates
`the maximal efficacy of a drug; and the qJ..Iantal dose(cid:173)
`effect curve indicates the potential variability of re(cid:173)
`sponsiveness among individuals.
`
`Variation in Drug Responsiveness
`Individuals may vary considerably in their respon(cid:173)
`siveness to a drug; indeed, a single individual may re(cid:173)
`spond differently to the same drug at different times
`during the course of treatment. Occasionally, indi(cid:173)
`viduals exhibit an unusual or idiosyncratic drug re(cid:173)
`sponse, one that is infrequently observed in most pa(cid:173)
`tients. The idiosyncratic responses are usually caused
`by genetic differences in metabolism of the drug or
`
`DRUG RECEPTORS & PHARMACODYNAMICS I 29
`
`by immunologic mechanisms, including allergic reac(cid:173)
`tions.
`Quantitative variations in drug response are in gen(cid:173)
`eral more common and more clinically important: An
`individual patient is hyporeactive or hyperreactive
`to a drug in that the intensity of effect of a given dose
`of drug is diminished or increased in comparison to
`the effect seen in most individuals. (Note: The term
`hypersensitivity usually refers to allergic or other
`immunologic responses to drugs.) With some drugs,
`the intensity of response to a given dose may change
`during the course of therapy; in these cases, respon(cid:173)
`siveness usually decreases as a consequence of
`continued drug administration, producing a state of
`relative tolerance to the drug's effects. When respon(cid:173)
`siveness diminishes rapidly after administration of a
`drug, the response is said to be subject to tachyphy(cid:173)
`laxis.
`The general clinical implications of individual
`variability in drug responsiveness are clear: The phy(cid:173)
`sician must be prepared to change either the dose of
`drug or the choice of drug, depending upon the re(cid:173)
`sponse observed in the patient. Even before adminis(cid:173)
`tering the first dose of a drug, the physician should
`consider factors that may help in predicting the direc(cid:173)
`tion and