siroors

1Pharmacodynamics: Receptorsand Concentration-Response

Relationships

SITES OF DRUG ACTION

For most drugs, the site of action is a specific macromole-cule, generally termed a receptor or a drug target,which may be a membrane protein, a cytoplasmic or ex-tracellular enzyme, or a nucleic acid. A drug may showorgan or tissue selectivity as a consequence of selectivetissue expression of the drug target. For example, theaction of the proton pump inhibitor esomeprazole occursspecifically in the parietal cells that line the gastric pits ofthe stomach because that is where its target, the potas-sium/hydrogen adenosine triphosphatase (K+/H+-ATPase),is expressed. Although the actions of a few drug types, suchas osmotic diuretics (see Chapter 21), may not involvereceptors as they are usually defined, the concept of recep-tors as sites of drug action is critical to understandingpharmacology.

Receptors (i.e., drug targets) fall into many classes, buttwo types predominate:

� Molecules, such as enzymes and deoxyribonucleic acid(DNA), which are essential to a cell’s normal biologicalfunction or replication, and

� Biological molecules that have evolved specifically forintercellular communication.

The former molecules could be considered general-ized and the latter specialized receptors. Generalizedreceptors can include biological molecules with any func-tion, including enzymes, lipids, or nucleic acids. The ear-lier example of the parietal cell K+/H+-ATPase is an exampleof this type of drug target. Specialized receptors includemolecules like ion channels and proteins in the plasmamembrane, designed to detect chemical signals and initi-ate a cellular response via activation of signal transductionpathways. The biological function of these molecules is torespond to neurotransmitters, hormones, cytokines, andautocoids and convey information to the cell, resultingin an altered cellular response. These types of receptorsare the primary targets of most drugs in clinical use.

The concept of receptors was first proposed more than acentury ago by the German chemist Paul Ehrlich, who wastrying to develop specific drugs to treat parasitic infections.He proposed the idea of specific ‘‘side chains’’ on cells thatwould interact with a drug, based on mutually complemen-tary structures. Each cell would have particular character-istics to recognize particular molecules. He proposed that adrug binds to a receptor much like a key fits into a lock.

This lock and key hypothesis is still relevant to howwe understand receptors today. It emphasizes the ideathat the drug and receptor must be structurally comple-mentary to recognize each other and initiate an effect.

The specificity of such interaction raises the concept ofmolecular recognition. Drug receptors or targets musthave molecular domains that are spatially and energeti-cally favorable for binding specific drug molecules. It isnot surprising that most receptors are proteins, becauseproteins undergo folding to form three-dimensional struc-tures that could easily be envisioned to complement thestructures of drug molecules. Enzymes are also reasonablycommon drug targets, although they fall under the gener-alized receptor class discussed.

The vast majority of drugs are small molecules withmolecular weights below 500 to 800. These moleculesinteract with their protein targets via a number of differentchemical bonds. The principal types of chemical bonds aredepicted in Figure 1-1. These bonds apply to the interac-tions between drugs and classical receptors. Covalentbonds require considerable energy to break and are classi-fied as irreversible when formed in drug-receptor com-plexes. Ionic bonds are also strong but may be reversedby a change in pH. Most drug-receptor interactions involvemultiple weak bonds.

AGONISTS AND ANTAGONISTS

Molecules that bind to receptors may have two majoreffects on the conformation of the receptor molecule.Agonists will bind to the receptor and activate it, like a

ABBREVIATIONS

b-ARK b adrenergic receptor kinasecAMP Cyclic adenosine monophosphateGABA g-aminobutyric acidGABAA g-aminobutyric acid type A

receptorGPCR G-protein–coupled receptorLGIC Ligand-gated ion channelEpi EpinephrineNE NorepinephrineRTK Receptor tyrosine kinase

3

key will fit into a lock and turn it. Activation of the recep-tor by agonist binding initiates a conformational changein the receptor and activation of one or more downstreamsignaling pathways. An example of the action of an agonistis provided by the effect of acetylcholine on the nicotiniccholinergic receptor at the neuromuscular junction. Whenacetylcholine binds to its binding sites on the externalsurface of this receptor, the channel opens and allowsNa+ to flow down its electrochemical gradient and depo-larize the muscle cell.

Antagonists are drugs that bind to the receptor butdo not have the unique structural features necessary toactivate it. In the lock and key analogy, antagonists canfit in the lock but cannot open it. Like agonists, antago-nists fit into a specific binding site within the receptorbut lack the proper structural features to initiate a confor-mational change leading to receptor activation. However,because they occupy the binding site of the receptor,antagonists inhibit activation by agonists. An exampleof antagonists is the class of neuromuscular blocking drugsused in the operating room to relax skeletal muscles duringsurgery. These drugs are analogs of curare, the active mol-ecule in plant extracts used as arrow poisons by NativeSouth Americans and studied by early European explorers.Curare is an antagonist at nicotinic cholinergic receptorsat the neuromuscular junction and blocks the ability ofacetylcholine or similar agonists to activate this receptor.This blockade inhibits muscle depolarization and causesparalysis of skeletal muscle, including the diaphragm andintercostal muscles needed for respiration. Several modernanalogs of curare are available and used routinely duringgeneral anesthesia for relaxing muscle tone in patientsundergoing surgery (see Chapter 12).

A third class of drugs that interact with receptors areallosteric modulators. These compounds bind to asite on the receptor distinct from that which normally

binds agonist, called an allosteric site. Occupation ofthis site can either increase or decrease the response tothe natural agonist, depending on whether it is a positiveor negative modulator. Because allosteric modulators bindto sites different from where agonists bind, interactionsbetween agonists and allosteric modulators are not com-petitive. The binding sites for agonists, antagonists, andallosteric modulators are depicted in Figure 1-2.

RECEPTORS

Receptors are a primary focus for investigating themechanisms by which drugs act. With the sequencing ofthe human genome, the structures and varieties of mostreceptors have now been identified. This advance hasrevealed many new receptors that could be potentialdrug targets for further pharmaceutical development. Themajor features of receptors are listed in Box 1-1. Threemajor concepts are illuminated by the concept of drugreceptors.

The first is the quantitative relationship betweendrug concentration and the subsequent physiologicalresponse. This response is determined primarily by theaffinity of the drug for the receptor, which is a measureof the binding constant of the drug for the receptor pro-tein. A high affinity means that a low concentration ofdrug is needed to occupy receptor sites, whereas a lowaffinity means that much higher concentrations of drug

N

N O C

C

H

H H HH

NC

N CO

O+ −

Decreasingbond

strength

Covalent

Ionic

Hydrogen

Hydrophobic

van der Waals

FIGURE 1–1 Types of chemical bonds and attractive forces betweenmolecules that are pertinent to the interaction of drugs with their active sites.

Allostericantagonist

Antagonist AgonistsAllostericactivator

Extracellular

Intracellular

Signal

Other drugs

FIGURE 1–2 Major features of receptors depicting binding sites foragonists, antagonist, and allosteric modulators. Receptors embedded in cellmembranes generally extend further on both the extracellular and intracellularsides. Attached to these proteins on the extracellular side are carbohydrate(glycosylation) chains. Shown are binding sites on the extracellular side forbinding two molecules of an endogenous transmitter (dark blue symbols) toactivate the transmembrane receptor. Agonists and antagonists compete withthe endogenous transmitter for binding sites. Allosteric agonists (activators) orantagonists enhance or block the signal, respectively, by binding to allostericsites that influence (wavy line) signal transmission. Other drugs can block signaltransmission within the membrane or at intracellular signal reception points.The arrows indicate the direction of communication to the other side of themembrane.

4 General Principles

are needed. The concentration-response curve is also influ-enced by the number of receptors available for binding.In general, more receptors can produce a greater response,although this is not always the case.

The second key concept is that receptors and their dis-tribution in the tissues of the body are responsible for thespecificity of drug action. The size, shape, and charge of areceptor determine its affinity for binding any of the vastarray of chemically different hormones, neurotransmitters,or drug molecules it may encounter. If the structure of thedrug changes even slightly, the type of receptor the drugbinds to will also often change. Drug binding to receptorsoften exhibits stereoselectivity, in which stereoisomersof a drug that are chemically identical, but have differentorientations around a single bond, can have very differentaffinities. For example, the L-isomer of narcotic analgesicsis approximately 1000 times more potent than the D-isomer, which is essentially inactive for pain relief (seeChapter 36). The presence or absence of a single hydroxylgroup, methyl group, or other apparently minor structuralchange can also dramatically alter the affinity of a drug fora receptor.

Receptors also explain the key concept of pharmacolog-ical antagonists, which prevent agonist activation by bind-ing to a receptor. Administration of an antagonist willblock tonic or stimulated activity of endogenous neuro-transmitters and hormones, thus interfering with theirnormal physiological functions. An example is proprano-lol, which, by antagonizing b1 adrenergic receptors, pre-vents the normal increase in heart rate associated withactivation of the sympathetic nervous system (seeChapter 11).

Specialized receptors are usually involved in the normalregulation of cell function by hormones, neurotransmit-ters, growth factors, steroids, and autocoids. Althoughthey are often found on the cell surface, where they areeasily accessible to hydrophilic messengers, many hor-mone receptors are located inside the cell, and ligandsfor these molecules easily cross the cell membrane (seePart V). An example of an intracellular receptor is the glu-cocorticoid receptor (see Chapter 39). For most receptortypes, multiple distinct subtypes can cause similar or dis-tinct responses. This diversity of receptors and responsesprovides new targets for drug development.

LIGAND-RECEPTOR INTERACTIONS

In most cases, a drug (D) binds to a receptor (R) in areversible bimolecular reaction described as:

(1-1)D þ R�DR�DR�!!!Response

Occupancy of the receptor by the drug may or may notalter its conformation. Antagonists participate only in thefirst equilibrium as they bind to the receptor and occupythe binding site. Agonists, on the other hand, have theappropriate structural features to force the bound receptorinto an active conformation (DR*). Therefore agonists par-ticipate in both equilibria, binding to the receptor andinitiating a conformational change. This conformationalchange leads to a series of events causing a cellularresponse. It is important to remember that the DR complexis usually reversible for both agonists and antagonists.

RECEPTOR SUPERFAMILIES

Four major superfamilies of receptors are involved in signaltransduction, representing the targets of clinically usefuldrugs. These include ligand-gated ion channels(LGICs), G-protein–coupled receptors (GPCRs),receptor tyrosine kinase (RTKs), and nuclear hor-mone receptors. Table 1-1 contains a list of receptors

TABLE 1–1. Examples of Specialized Receptors

Type Subtype Endogenous Ligand

LGICs

Acetylcholine Nicotinic AcetylcholineGABA A, C GABAGlutamate NMDA, kainate,

AMPAGlutamate or aspartate

Serotonin 5-HT3 Serotonin

GPCRs

ACTH - ACTHAcetylcholine Muscarinic AcetylcholineAdrenergic a1-2, b1-3 Epi and NEGABA B GABAGlucagon - GlucagonGlutamate Metabotropic GlutamateOpioid m, k, d EnkephalinsSerotonin 5-HT1-2,4,5-7 5-HTDopamine D1-5 DopamineAdenosine A1, A2a, A2b, A3 AdenosineHistamine H1-4 Histamine

RTKs

Insulin - InsulinNGF - NGFEGF - EGF

Nuclear Hormone Receptors

Estrogen a, b EstrogenGlucocorticoid - CortisolAndrogens - Testosterone

ACTH, Adrenocorticotrophic hormone; EGF, epidermal growth factor; Epi,epinephrine; NGF, nerve growth factor; NE, norepinephrine.

BOX 1–1 Features of Receptors

Protein: Lipoprotein, glycoprotein with one or more subunitsMolecular weights of 45-200 kDaDifferent tissue distributionsDrug binding is usually reversible and stereoselectiveSpecificity of binding not absolute, leading to nonspecific

effectsReceptors are saturable because of their finite numberAgonist activation results in signal transductionMay require more than one drug molecule to activate receptorMagnitude of signal depends on degree of bindingSignal can be amplified by intracellular mechanismsDrugs can enhance, diminish, or block signal generation or

transmissionCan be up regulated or down regulated

CHAPTER 1 Pharmacodynamics: Receptors and Concentration-Response Relationships 5

in these classes that are important in the actions of severaltherapeutically useful drugs.

LGICs are most important in the central and peripheralnervous systems, excitable tissues such as the heart, andthe neuromuscular junction. They include nicotinic cho-linergic receptors (Fig. 1-3) at the neuromuscular junction,many of the g-aminobutyric acid (GABA) and glutamatereceptors in the brain, and one type of serotonin receptor.These receptors are responsible for fast synaptic transmis-sion, where release of a transmitter causes an electricaleffect on the postsynaptic neuron by opening a specificion channel and leading to a change in membrane poten-tial. LGICs are complex proteins composed of four or fivesubunits, and the specific subunit combinations differ atdifferent sites in the body, allowing for selectivity ofeffects.

For example, the subunits of the nicotinic receptor atthe neuromuscular junction differ from those of the nico-tinic receptor at autonomic ganglia. As a consequence,although the responses to acetylcholine and ion gatingproperties of these two channels are similar, these recep-tors are activated and antagonized by different drugs. Thisproperty allows selective blockade of the neuromuscularjunction by drugs that do not block the channel at auto-nomic ganglia (see Chapter 12). Typically, LGICs have twobinding sites for agonist and binding sites for allostericmodulators, which increase or decrease the ability of thetransmitter to open the channel. One important class ofallosteric modulators is the benzodiazepines, which areused extensively for the treatment of anxiety and

sleep disorders (see Chapter 31). These drugs bind to g-ami-nobutyric acid type A (GABAA) receptors, which are ligand-gated chloride ion channels that are activated by the inhib-itory neurotransmitter GABA. Benzodiazepines have noeffect on channel opening by themselves, but their bind-ing dramatically increases the ability of GABA to open thechannel.

GPCRs are probably the most important class of recep-tors in pharmacology, because most currently marketeddrugs target this receptor superfamily. GPCRs are muchsimpler than ligand-gated ion channels, being usuallycomposed of a single subunit that contains seven trans-membrane spanning domains. They are thought to havea single binding site, and as yet, there are only a few allo-steric modulators for this class of receptors. GPCRs activatesignals by inducing a conformational change that activatesa large family of G-proteins to regulate signaling pathways(Fig. 1-4). These events regulate a host of important cellularfunctions (Box 1-2). GPCRs represent the largest proteinfamily in the human genome, accounting for approxi-mately 2% of all human genes. Approximately half ofthese receptors are olfactory receptors for detecting odor-ants; most of the remaining GPCRs respond to neurotrans-mitters, hormones, autocoids, and cytokines.

RTKs contain an extracellular ligand binding domain,one transmembrane spanning segment, and an intracellu-lar tyrosine kinase domain. Binding of a ligand to theextracellular domain causes dimerization of the receptorand stimulates a tyrosine kinase activity within the intra-cellular domain. The best examples of these receptors arethe growth factor receptors such as epidermal growthfactor or nerve growth factor receptors (Fig. 1-5). Whengrowth factors bind to these receptors, they cause tyrosinephosphorylation of the receptor, other proteins, or both,which leads to activation of a large number of cellularpathways. Cytokine receptors are part of this subfamilybecause they are structurally very similar. However, insteadof intrinsic enzymatic activity within the receptor mole-cule, they have docking sites where tyrosine kinaseenzymes bind (Fig. 1-6). These receptors are activated bya variety of molecules such as erythropoietin, interleukins,and growth hormone. RTKs are an increasingly importanttarget for drugs to treat neoplastic diseases, where cellgrowth is uncontrolled (see Chapters 53 and 54).

Nuclear hormone receptors are located in the cyto-sol, and unlike the other receptor superfamilies that areactivated on the cell surface, these receptors bind theirligand in the cytoplasm and translocate to the nucleus.Intracellular receptors respond to highly hydrophobiccompounds that easily cross cell membranes, includingvarious classes of steroids, but there are also nuclearreceptors for other compounds, such as retinoic acid.These receptors are usually ligand-activated transcriptionfactors that, when bound by ligand, dimerize, enter thenucleus, and bind directly to specific DNA recognitionsequences and increase or decrease transcription of partic-ular genes (Fig. 1-7).

OTHER TARGETS

In contrast to the four classes of specialized receptors thathave been honed by evolution to provide the selectivity

* *

αδ αγ

FIGURE 1–3 Crystal structure of the nicotinic cholinergic receptor. Bindingsites for acetylcholine are shown as asterisks, with the gating portions shownwith arrows. (From Unwin N. The Croonian Lecture 2000. Nicotinic acetylcholine receptor and

the structural basis of fast synaptic transmission. Philos Trans R Soc Lond B Biol Sci

2000;355:1813–1829.)


and specificity required for intercellular communication,there are also intracellular enzymes that provide drug tar-gets with excellent specificity. Two notable examplesinclude esomeprazole, which inhibits the parietal cell H+/K+-ATPase and is very useful for treatment of gastric

hyperacidity (see Chapter 18), and imatinib mesylate,which inhibits the abl tryrosine kinase and is useful inthe treatment of leukemias (see Chapter 55). Neither theH+/K+ -ATPase nor the abl tyrosine kinase are specializedreceptors for transmembrane signaling, but both are

Intracellular

Extracellular

Stimulatoryagonist Inhibitory

agonist

Effector(cyclase)

N

C C

N

I VII

II VIV

IVIII I

II

III

IV VI

V VIIGTP

GDPGTP

GDPATP

cAMP

+ −

γ γ

β β

αs αi

FIGURE 1–4 Structure of GPCRs and signaling molecules involved in regulation of adenylyl cyclase. Binding of the ligand to the stimulatory receptor (left)produces a conformation change that is transmitted to the a subunit of Gs. This activates Gs by exchanging bound guanosine 5’-diphosphate (GDP) with guanosine5’-triphosphate (GTP) to give active as. Gs dissociates, with active as activating the adenylyl cyclase. The bg subunits are released and freed for other signalingfunctions. Activation of an inhibitory receptor (right) causes GDP–GTP exchange on the ai subunit, which can inhibit the adenylyl cyclase.

BOX 1–2 GPCR Signaling

Agonist binding to GPCRs activates heterotrimeric G-proteinsto activate effector molecules, such as enzymes and channels.These G-proteins are located at the inner surface of the plasmamembrane and consist of a, b, and g subunits. The a subunit isa key component because:� It interacts specifically with receptors.� Upon activation, it exchanges bound guanosine 5’-dipho-

sphate (GDP) for guanosine 5’-triphosphate (GTP), under-goes a conformational change releasing the bg subunits,and interacts with effectors.� It has an intrinsic ability to hydrolyze bound GTP, which is

activated by regulatory proteins that aid in turning off thesignal.� aGDP binds to and sequesters the bg subunit. bg subunits

exist as dimers and can also activate certain effectors.Activated aGTP interacts directly with effectors, such as ad-enylyl cyclase (see Fig. 1-4) to regulate their activity andraise the concentration of a second messenger (see later).

Genes for 17 different G a subunits have been identified andcan be grouped into four families. Although there is great struc-tural homology between a subunits, each protein has uniqueregions that impart specificity to its interactions with receptorsand effectors. The C-terminal region displays the most variabil-ity and interacts with receptors. Generally, members within afamily have similar functional properties. The four families are:

� Gs, which activates adenylyl cyclase.� Gi, which inhibits adenylyl cyclase. This family also includes

Go, which regulates ion channels, and Gt, which couples rho-dopsin to a phosphodiesterase in the visual system.� Gq, which activates phospholipase C-b.� G12/13, which activates small G proteins, such as Rho.

The b and g subunits of G-proteins form a tightly associated func-tional unit and are also characterized by multiple genes. There are 7b and 12 g subunits known. When bg is released from the a subunitby GTP binding, bg subunits also regulate effectors, such as ionchannels, and enzymes, such as adenylyl cyclase or phospholipaseC-b. bg also activates muscarinic K+ channels in cardiac and neuralcells and is an important inhibitor of L and N type Ca++ channels inneurons.

Activation of many G-proteins raises the level of ‘‘second messen-gers’’ in target cells. A second messenger is a small molecule, such ascyclic AMP, Ca++ or K+ ions, inositol trisphosphate, or diacylglycer-ol. These often activate protein kinases that produce responses byphosphorylating other regulatory proteins. Cyclic AMP activates acyclic AMP-dependent protein kinase; inositol trisphosphate (byreleasing Ca++) activates many Ca++ and calmodulin-dependentprotein kinases, and diacylglycerol activates protein kinase C.This phosphorylation leads to either activation or inactivation ofdownstream pathways and produces the characteristic response ofthe cells to receptor activation.


central to control of a primary function in the cells inwhich they are expressed. Thus both of these drugs actwith excellent specificity.

RECEPTOR CLASSIFICATION

For each type of hormone, neurotransmitter, growthfactor, or autocoid, there is at least one specific receptor.Although it was first thought that there was a single recep-tor for each messenger, it is now clear that in most casesthere is a family of receptors with multiple subtypes.Some of these families are quite large. For example,14 known receptors respond specifically to serotonin,9 to epinephrine (Epi) and norepinephrine (NE), morethan 20 to acetylcholine, and 25 to 30 to glutamate.Although the evolutionary pressure leading to the contin-ued existence of so many receptors is not understood, itis clear that there can be complexity, redundancy, andmultiplicity in the effects of a single agonist. Thereforeunderstanding the tissue distribution and biology ofthese different receptor isoforms is an important goalthat will allow development of specific drugs for each

novel target. This strategy will provide opportunitiesfor obtaining specific therapeutic responses withoutunwanted side effects.

Receptors are commonly named after the natural ago-nist that activates them. For example, acetylcholine actsthrough cholinergic receptors; Epi (adrenaline) and NE(noradrenaline) act through adrenergic receptors; and sero-tonin acts through serotonergic receptors. Receptor activa-tion is very specific, and there is little cross-reactivitybetween natural compounds and other receptors. Forinstance, acetylcholine binds only to cholinergic receptorsand does not bind to adrenergic receptors or members ofother receptor families. This is true for essentially all trans-mitters and hormones. However, a transmitter like dopa-mine (the immediate precursor of NE), which has its ownfamily of dopaminergic receptors, also binds with lowaffinity to adrenergic receptors as a consequence of itsstructural similarity to NE. This is advantageous, becausedopamine is used clinically to stimulate b1 adrenergicreceptors in cardiac failure (see Chapter 11).

As mentioned, each receptor family typically containsmultiple subtypes that may be characterized pharmacolog-ically by the use of selective agonists, antagonists, or

PP

P

PI3 kinase

SH2PTPase

P

GF

Kinase

PLC γ

Elk-1

Jun

SH2

SH3

Grb2

mSOS

GTPGDP

ras raf-1

MEK

MAP kinase

Nucleus

Growthfactor

Growthfactors

ras

TNF, IL-1stress

rac?

JNK

Nuclear events

MEKK1

UV

?

MEKK3

SEK-1

raf

MEK

MAP kinase p38 MAP kinase

A BFIGURE 1–5 Pathways used by growth factors, stressors, and ultraviolet radiation to regulate cell function. A, Example of the mechanism used by growth factors(GF) to activate mitogen-activated protein kinases (MAP kinase). Binding of the GF induces dimerization of the receptor, thereby activating its kinase, which leads tophosphorylation of the receptor (P) on tyrosine residues. This creates binding sites for SH2 domains of multiple signaling proteins (PI 3 kinase, Grb2, PLC g, and anSH2-containing tyrosine phosphatase [SH2 PTPase] are shown). The interaction between Grb2 and the mSos protein activates ras, leading to activation of the MAPkinase cascade. B, The similarity of the protein kinase cascades used by growth factors, stressors, and ultraviolet radiation, leading to the activation of MAP kinaseand two related kinases, the Jun N-terminal kinase (JNK) and p38 MAP kinase; rac, a low molecular weight G-protein in the ras superfamily; MEKK1 and MEKK3, twoMEK kinases analogous in function to raf-1 but with differing substrate specificities; SEK-1, a kinase analogous to MEK that phosphorylates and activates JNK.


both. For example, there are two major subfamilies of cho-linergic receptors, nicotinic and muscarinic. Nicotinic cho-linergic receptors are selectively activated by the agonistnicotine and are selectively blocked by drugs like curare.In contrast, muscarinic cholinergic receptors are selectivelyactivated by the agonist muscarine and are selectivelyblocked by the antagonist atropine (see Chapter 10).Nicotine and curare have essentially no effect on musca-rinic cholinergic receptors, and muscarine and atropinehave essentially no effect on nicotinic cholinergic recep-tors. Both nicotinic and muscarinic cholinergic receptorsubfamilies, like that for most other neurotransmitters,consist of multiple subtypes. These are discussed in subse-quent chapters.

The situation is complicated because multiple receptorsubtypes for one transmitter can coexist on a single cell,raising the possibility that one transmitter can deliver mul-tiple messages to the same cell. These messages may beopposing, complementary, or independent. For example,various combinations of adrenergic receptors can be pres-ent on the same cell. The b1 adrenergic receptor activatesadenylyl cyclase through a G-protein (Gs). Because thea2 adrenergic receptor inhibits adenylyl cyclase through adifferent G-protein (Gi), mutually antagonistic signals willbe generated by the presence of both subtypes in responseto the same neurotransmitter, NE. In a like manner,additive signals can be generated by the presence of theb2 adrenergic receptor, which also activates adenylylcyclase through Gs, or independent signals can be gener-ated by the presence of the a1 adrenergic receptor, whichactivates phospholipase C (Fig. 1-8). Overall, the response

of a cell to a single transmitter (or a drug that mimics aneurotransmitter) depends on the types and relative pro-portions of receptor subtypes present in the cell.

CONCENTRATION-RESPONSERELATIONSHIPS

Binding of a drug to a receptor is a reversible bimolecularinteraction, as described in Equation 1-1. This equationfollows the law of mass action, which states that atequilibrium, the product of the active masses on one sideof the equation divided by the product of active masses onthe other side of the equation is a constant. Therefore con-centrations of both drug and receptor are important indetermining the extent of receptor occupation and subse-quent tissue response.

Quantification of the amount of drug necessary to pro-duce a given response is referred to as a concentration–response relationship. Practically, one rarely knows theconcentration of drug at the active site, so it is usuallynecessary to work with dose-response relationships. Thedose of a drug is simply the amount administered (e.g.,10 mg), whereas the concentration is the amount perunit volume (e.g., mg/ml). To achieve similar concentra-tions in patients, it is often necessary to adjust the dosebased on patient size, weight, and other factors (seeChapter 3).

Dose-response curves are usually assumed to be at equi-librium, or steady-state, when the rate of drug influxequals the rate of drug efflux, although this is an idealthat is not often achieved in practice. Once the drugreaches its receptors, many responses are graded; that is,they vary from minimum to maximum response. Mostconcentration- and dose-response curves are plotted onlog scales rather than linear scales to make it easier to

Nucleus

↑ Transcription

IL

JAK

STATs STATs STATs

JAK P P

P P

JAK

GH or IL

β

α

β β

α α

FIGURE 1–6 The pathways used by growth hormone, interferons, andcytokines to regulate nuclear events. The two isoforms of the receptor, a and bare shown, with the Janus kinase (JAK) bound to the b form. The cytoplasmicsignal transducers and activators of transcription (STAT) proteins are shown asovals. Activation of the receptor by growth hormone (GH) or cytokines, such asinterleukins (IL), leads to dimerization and phosphorylation of the JAK and STATproteins on tyrosine residues. The STAT proteins translocate to the nucleus andactivate transcription of certain genes.

H

H

Hormone

HREsequence

Promotersequence

LBD

LBD Ligand binding domain

DBD DNA binding domain

LBD

Transcriptionfactors

Transcription

DNA

RNApolymerase

H

DBD DBD

FIGURE 1–7 Members of the steroid receptor family bind to DNA at thehormone response element (HRE) and facilitate (or inhibit) formation of activetranscription complexes at the promoter. Binding of the hormone (H) to theligand-binding domain (LBD) causes translocation of the protein to the nucleus,dimerization, and the formation of a complex of proteins with the DNA-bindingdomain (DBD) binding to the HRE and activating the promoter.


compare drug potencies; the log scale yields an S-shapedcurve, as shown (Fig. 1-9).

Quantal responses are all-or-none responses to a drug.For example, after the administration of a hypnotic drug, apatient is either asleep or not. Construction of dose-response curves for quantal responses requires the use ofpopulations of subjects who are characterized by interindi-vidual variability. A few subjects demonstrate an initialresponse at a low dose, most subjects demonstrate an ini-tial response at an intermediate dose, and a few subjectsdemonstrate an initial response at a high dose (Fig. 1-10,A), resulting in a bell-shaped ‘‘Gaussian’’ distribution ofsensitivity. Quantal dose-response curves are often plottedin a cumulative manner, comparing the dose of drug onthe x-axis with the cumulative percentage of subjectsresponding to that dose on the y-axis (Fig. 1-10, B).

Occupation of a receptor by a drug is derived from themass action law (see Equation 1-1) and is:

(1-2)½DR�

½RT�¼

½D�

½D� þ KD

where RT represents the total number of receptors and KD isthe equilibrium dissociation constant (or affinity constant)of the drug for the receptor. Therefore the proportion ofdrug bound, relative to the maximum proportion thatcould be bound, is equal to the concentration of drugdivided by the concentration of drug plus its affinity con-stant. It is important to note that [DR]/[RT] describes theproportion of receptors bound, or fractional occu-pancy, which ranges from zero when no drug is boundto one when all receptors are occupied by drug. This equa-tion can be used to calculate what proportion (not actualnumber) of receptors will be occupied at a particular con-centration of drug and demonstrates that fractional occu-pancy depends only on the concentration of drug and itsaffinity constant, not on total receptor number.

The KD value is a fixed parameter describing theaffinity of a drug for the receptor binding site. FromEquation 1-2, it is clear that when KD equals [D], half of

β1 α2

Gs

AC

Gi

β1 β2

Gs Gs

AC

β1 α1

Gs Gq

AC PLC

Opposing

ATP

NE

cAMP+ + − +

Additive

ATP

NE

cAMP+ + + +

Independent

ATP PIP2 DAGIP3

NE

cAMP++ + +

FIGURE 1–8 Activation of multiple receptors by a single transmitter:effects on signal transduction. Coactivation of more than one receptor subtypefor NE can result in second-messenger responses, which are opposing, additive,or independent. G-proteins shown for stimulatory (Gs), inhibitory (Gi), andphospholipase (Gq). NE, Norepinephrine; AC, adenylyl cyclase; ATP, adenosinetriphosphate; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate;IP3 , inositol 1,4,5-trisphosphate; DAG, 1,2-diacylglycerol.

Concentration (nM) Concentration (nM)

200

20

40

60

80

100

0

20

40

60

80

100

40 60 80 100 1.00.10 10 100

% M

axim

al r

espo

nse

KD(app)

KD(app)

Nearlylinear

inthis

region

A B

FIGURE 1–9 Concentration-response curve for receptor occupancy. A, Arithmetic scale. B, Logarithmic concentration scale. KD (app) is the concentration of drugoccupying half of the available receptor pool.


the receptors are occupied; thus KD is the concentration ofdrug that achieves half maximal saturation of the receptorpopulation. This means that drugs with a high KD (lowaffinity) will require a high concentration for occupancy,whereas drugs with a low KD (high affinity) require lowerconcentrations. KD is also equal to the ratio of the rate ofdissociation of the [DR] complex to its rate of formation.Thus the KD of a drug is a reflection of the structural affin-ity of the drug and its receptor, that is, how quickly thedrug binds to the receptor and how long it stays bound.Every drug/receptor combination will have a characteristicKD, although these values can differ by many orders ofmagnitude. For example, glutamate has approximatelymillimolar affinity for its receptors, whereas some b adren-ergic antagonists have nanomolar affinities for theirreceptors.

ANTAGONISTS

There are two major classes of antagonists, competitiveand noncompetitive. Most antagonists are competitiveantagonists. These drugs compete with agonists for thesame binding site on a given receptor. If the receptor isoccupied by a competitive antagonist, then agonist bind-ing to the receptor is reduced. Likewise, if the receptor isbound by an agonist, antagonist binding will be dimin-ished. When present alone, each drug will occupy thereceptors in a concentration-dependent manner asdescribed in Equation 1-2. However, when both drugs arepresent and competing for the same binding site, the equa-tion describing agonist occupancy is:

(1-3)½DR�

½RT�¼

½D�

½D� þ KDð1þ ½B�=KBÞ

where D represents agonist, B represents antagonist, andKD and KB represent their relative affinity constants. Thisequation demonstrates that in the presence of a competi-tive antagonist, the apparent affinity (KD) of the agonist[D] for the receptor is altered by the factor 1 + [B]/KB. As theconcentration of the antagonist increases, more agonist isrequired to cause an effect. Therefore a competitive antag-onist reduces the response to the agonist. However, if theconcentration of the agonist is increased, it can overcomethe receptor blockade caused by the competitive antago-nist. In other words, blockade by competitive antagonistsis surmountable by increasing the concentration of ag-onist. With two drugs competing for the same binding site,the drug with the higher concentration relative to its affin-ity constant will dominate. It is important to rememberthat the key factor is the ratio of the drug concentrationrelative to its affinity constant, not simply drugconcentration.

Equation 1-3 also demonstrates the very importantpoint that the presence of a competitive antagonistcauses a shift to the right in the agonist dose-responsecurve (decreased apparent KD) but no change in theshape of the curve. This parallel rightward shift isdiagnostic of competitive antagonists and means thatevery portion of the dose-response curve is shifted byexactly the same amount (Fig. 1-11). The magnitude ofrightward shift is dependent on the concentration ofantagonist, which is variable, divided by its affinity con-stant, which is fixed. Therefore, if the concentration ofdrug is known, measuring the magnitude of the rightwardshift allows direct calculation of the KB for the antagonist.This is very important because the affinity constant isessentially a molecular description of how well a drugbinds to a particular receptor and is constant for anydrug/receptor pair. Thus comparison of affinity constantsfor antagonists at receptors in different tissues is the bestway to determine whether they are the same or different,making antagonists extremely useful in subclassifyingreceptors.

The second, less common type of antagonist is the non-competitive antagonist. There are a number of differentnoncompetitive antagonists, but most drugs in this classare irreversible alkylating agents. An example of thisclass of drug is phenoxybenzamine, a drug that acts pre-dominantly on a1 adrenergic receptors and is used to mit-igate the effects of catecholamines secreted by adrenal

12

8

4

0

90

70

40

10

1.0 2.0 3.0 4.0 5.0

1.0 2.0 3.0 4.0 5.0

1.0 2.0 3.0 4.0 5.0

Num

ber

resp

ondi

ngC

umul

ativ

e re

spon

ding

(%

)

Dose (mg/kg)

Dose (mg/kg) (B-1)

Dose (mg/kg) (log scale) (B-2)

A

B

ED95

B-1

B-2

ED50

ED10

2s 2s1s 1sm

FIGURE 1–10 Quantal effects. Typical set of data after administration ofincreasing doses of drug to a group of subjects and observation of minimumdose at which each subject responds. Data shown are for 100 subjects. Mean(m) and median dose is 3.0 mg/kg; standard deviation (s) is 0.8 mg/kg. A,Results plotted as histogram (bar graph) showing number responding at eachdose; smooth curve is normal distribution function calculated for m of 3.0 ands of 0.8. B, Data from A replotted as a cumulative percentage respondingversus dose with dose shown in B-1 on arithmetic scale (as in A) and in B-2on a logarithmic scale. ED (effective dose) values are shown for doses at which10%, 50%, or 95% of subjects respond.


tumors (see Chapter 11). Drugs of this class contain highlyreactive groups, and when they bind to receptors, theyform covalent bonds, occupying the binding site in anessentially irreversible, nonsurmountable manner.Because they decrease the number of available receptors,noncompetitive antagonists will usually decrease the max-imum response to an agonist without affecting its EC50

(concentration causing half-maximal effect). An advantageof a noncompetitive antagonist is its long-lasting effect.Because the drug binds a receptor irreversibly, the drugeffect lasts until new receptors are synthesized.

PARTIAL AGONISTS

As discussed, agonists can participate in both equilibriashown in Equation 1-1, binding to and activating receptorsto cause a conformational change. Partial agonists havea dual activity, that is, they act partially as agonists andpartially as antagonists. When bound to their receptors,partial agonists are only partly able to shift the receptorto its activated conformational state. Efficacy is theproportion of receptors that are forced into their activeconformation when occupied by a particular drug. It isused to describe the maximal effect of partial agonists incausing a receptor conformational change and can rangefrom 0 to 1. Drugs with full efficacy are called ‘‘full ago-nists,’’ drugs with some efficacy are ‘‘partial agonists,’’whereas drugs with zero efficacy are ‘‘antagonists.’’

Partial agonists can also partially inhibit the response tofull agonists acting at the same receptor type (Fig. 1-12). Ifboth full and partial agonists are present, as the concentra-tion of partial agonist is increased, more receptors will beoccupied by the partial agonist. This will cause a decreasein response, because some of the receptors will no longerbe activated. At very high concentrations of partial agonistrelative to its affinity constant, all of the receptors will beoccupied by partial agonist, and the full agonist becomes

essentially irrelevant. Therefore a diagnostic feature of apartial agonist is that it inhibits the action of a full agonistto the level of its own maximal effect.

SIGNAL AMPLIFICATION—SPARERECEPTORS

In some cases the response elicited by a drug is propor-tional to the fraction of receptors occupied. More com-monly, a maximal response can be achieved when only asmall fraction of receptors are occupied by an agonist. Thisphenomenon defines the concept of spare receptors, ora receptor reserve. The reason for this behavior is that thereare several intervening amplification steps downstreamfrom the initial receptor-triggering event. If there were a1:1 stochiometry between GPCR activation and G-proteinstimulation, for example, the existence of 10,000 receptorsand only 1000 G-proteins in a particular cell would resultin only 10% of receptors needing to be activated to cause afull response. Further receptor occupancy would not resultin an increase in the magnitude of response. When thesignaling pathways involve amplification steps, the EC50

for an agonist may be much lower than the concentrationneeded to cause half maximal receptor occupation (KD).

Spare receptors are important in all-or-none responses,where it is especially important that activation does notfail (e.g., the neuromuscular junction or the heart). Thepresence of spare receptors shifts the agonist dose-response curve to the left of the KD for binding ofagonist to receptor, and the degree of shift is proportionalto the proportion of spare receptors (Fig. 1-13). Thus sparereceptors make a tissue more sensitive to an agonist with-out changing its affinity for the receptor. Because the exis-tence of spare receptors is fairly common, the EC50 for an

100

80

60

40

20

0

1 10

AGalone

Concentration (log scale)

% M

axim

al r

espo

nse

AG inpresenceof ANT

FIGURE 1–11 Competitive antagonism; both the agonist (AG) and theantagonist (ANT) compete and bind reversibly to the same receptor site. Thepresence of the competitive antagonist causes a parallel shift to the right inthe concentration-response curve for the agonist.

100

50

78 56

Oxymetazoline alone

– log [Oxymetazoline] (M)

Plus epinephrine

% M

axim

al r

espo

nse

to e

pine

phrin

e

FIGURE 1–12 Partial agonists, such as the nasal decongestantoxymetazoline, give maximal responses that are lower than those of fullagonists, such as Epi, in vascular smooth muscle. At high enough concentrationsof oxymetazoline, the effect of Epi is reduced to the level of activity ofoxymetazoline alone.


agonist is usually not equal to its KD. For example, the b1

adrenergic receptor has the same chemical and physicalproperties in every tissue in which it is expressed.However, the EC50 for a particular drug in activatingresponses mediated by this receptor can vary by orders ofmagnitude in different tissues, depending on the degree ofreceptor reserve.

This means that if an agonist has a different EC50 in twodifferent tissues, one cannot conclude that the receptors inone tissue are different from the receptors in the othertissue, because there is no predictable relationship betweenEC50 and KD for a particular agonist/receptor combination.Spare receptors are also responsible for tissue specificactions of agonists. Because the presence of spare recep-tors increases the potency of an agonist, tissues with a highproportion of spare receptors will respond to agonists atlower concentrations, even if they contain exactly thesame receptor subtypes.

Spare receptors also complicate the analysis of partialagonists. If a drug is a partial agonist in one tissue, itmay be a full agonist in another tissue, which has ahigher proportion of spare receptors. In the GPCR exampledescribed, where only 10% of the receptors must be acti-vated to cause a full response, a weak partial agonist mayactivate this 10% and appear to be a full agonist. Because ofthis problem, a different term, intrinsic activity, is usedto describe the ability of a tissue to respond to agoniststimulation. Efficacy, which is the ability of the agonistto cause the receptor to assume an active conformation,is analogous to KD in that both are constant for a givendrug/receptor pair. It is an intrinsic property that dependson the structural complementarity of the drug and thereceptor molecules. Intrinsic activity, however, is highlycontext dependent. It varies in different tissues because

of the presence of different proportions of spare receptorsand downstream amplification mechanisms. A drug can bea partial agonist in efficacy, but a full agonist in intrinsicactivity when spare receptors are present.

RECEPTOR DESENSITIZATION ANDSUPERSENSITIVITY

The response of any cell to hormones or neurotransmittersis tightly regulated and can vary depending on other stim-uli impinging on the cell. Very often, the number of recep-tors in the membrane of a cell or responsiveness of thereceptors themselves is regulated. One hormone can sen-sitize a cell to the effects of another hormone, and morecommonly, when a cell is continuously exposed to stimu-lation by a transmitter or hormone, it may become desen-sitized. An example of this phenomenon is the loss of theability of inhaled b2 adrenergic agonists to dilate the bron-chi of asthmatic patients after repeated use of the drug (seeChapter 16). A hormone or agonist can affect the way a cellresponds to itself (homologous effects) or how it respondsto other hormones (heterologous effects). As an example ofthe latter phenomenon, exposure of a cell to estrogen sen-sitizes many cells to the effects of progesterone.

Changes in receptor binding affinity and signaling effi-ciency often occur rapidly. Receptor phosphorylation ofserines, threonines, or tyrosines is a common mechanismof regulating responsiveness. Phosphorylation can rapidlychange affinity or signaling efficiency and can also target areceptor for internalization and degradation.

The mechanisms involved in homologous and heterol-ogous desensitization of b2 adrenergic receptors are wellunderstood (Fig. 1-14). Receptor phosphorylation onserine-threonine residues by three different protein kinasesplays a role in the loss of responsiveness. These includeb adrenergic receptor kinase (b-ARK), cAMP-dependentprotein kinase, and protein kinase C. Phosphorylation ofthe b adrenergic receptor inhibits its ability to interact withG-proteins and subsequently leads to its sequestration orinternalization in a compartment where it cannot interactwith extracellular hormone. b-ARK is particularly impor-tant in homologous desensitization. It is capable only ofphosphorylating the active, agonist-bound form of thereceptor.

Other protein kinases, such as cAMP-dependent proteinkinase, may also prefer the agonist-bound form of thereceptor but not to the same extent as b-ARK. Althoughb-ARK was originally described as a kinase specific for theb adrenergic receptor, its specificity is not unique, in that alarge family of related protein kinases has been discovered.Between them, they can phosphorylate many differentG-protein–coupled receptors in their agonist-bound state.Phosphorylation inhibits the ability of the receptor tointeract with G proteins and subsequently leads to itssequestration or internalization in a compartment whereit cannot interact with extracellular hormone.

In the absence of hormone, most receptors are notlocalized to particular regions of the cell membrane.When a hormone binds, receptors rapidly migrate tocoated pits. These are specialized invaginations of themembrane surrounded by an electron-dense cage formedby the protein clathrin; this is where receptor-mediated

Concentration (nM) (log scale)

% M

axim

al r

espo

nse

100

80

60

40

20

0

A B C D

1.00.1 10 100

FIGURE 1–13 Logarithmic concentration–response curves for a singleagonist acting on the same receptor subtype in tissues with differentproportions of spare receptors (A, B, C, and D) and eliciting muscle contractionin vitro. Note that all tissues show the same maximum response to drug(intrinsic activity). The agonist shows its highest potency (lowest EC50) at thetissue with greatest proportion of spare receptors (A) and its lowest potency atthe tissue with the lowest proportion of spare receptors (D).


Heterologous

Homologous

Ligand

� receptor

�-ARK

p p

p

PGErec

p

cAMPkinase

cAMP

cAMP

AC

ACPKC PLCDAG

ATP

ATP

ER

Ca++

Gs

Gs

Gq

IP3

� receptor

�1 rec

�

cAMPkinase

FIGURE 1–14 Phosphorylation is important in receptor desensitization.Pathways of stimulation of b-ARK and cAMP-dependent protein kinase inhomologous desensitization, and cAMP-dependent protein kinase and proteinkinase C (PKC) in heterologous desensitization by a1 adrenergic receptor(�1 rec) and prostaglandin PGE receptor (PGE rec). AC, Adenylyl cyclase;DAG, diacylglycerol; ER, endoplasmic reticulum; G, G- protein; IP3, inositoltrisphosphate; p, phosphorylated state.

HormoneReceptor

Coated pitRecycling

CURLIntracellular pool

Internalization via receptor-mediated endocytosis

Small percentage

Recycling viaretroendocytosisVesicle

Dissociation

Low pH

Segregation

Lysosomes

Degradation

Hormonaldegradationproducts

Cell

Extracellular

pH4-5

Beforedrug

treatment

Normal receptors

Afterchronicagonist

Receptorsdown-regulated

Afterchronic

antagonist

Receptorsup-regulated

FIGURE 1–16 Long-term treatment with agonists or antagonists can alterpostsynaptic receptor density or responsiveness.

FIGURE 1–15 Pathways of receptor internalizationand recycling. CURL, Compartment of uncoupling ofreceptor and ligand.

endocytosis occurs. Segments of membranes within coatedpits rapidly pinch off to form intracellular vesicles rich inreceptor-ligand complexes (Fig. 1-15). Vesicles then fusewith tubular-reticular structures. In most cases dissociatedhormone is incorporated into vesicles that fuse with lyso-somes, with the hormone then degraded by lysosomalenzymes. Dissociated receptor recirculates to the cell sur-face. However, a fraction of internalized hormone may alsobe recirculated to the cell surface along with receptor, andthen released. This process is termed retroendocytosis. Freereceptors may recirculate to the cell surface or may besequestered temporarily in an intracellular membranecompartment. Alternatively, receptor may be transportedto lysosomes, where it is also degraded. The latter two casesresult in a net decrease in cell receptor number.

Finally, it is important to realize that the number ofreceptors in the plasma membrane of cells is not static(Fig. 1-16). Receptor number may be increased or decreasedunder the influence of hormonal mechanisms. Alteredreceptor number attributable to internalization or degrada-tion has an intermediate time course, whereas an alteredrate of receptor synthesis occurs more slowly. Receptorsmay also be up regulated, and this phenomenon canresult in receptor supersensitivity. Up regulation can

occur after exposure of the receptor to an antagonist, orinhibition of transmitter synthesis or release. In addition,other hormones can increase receptor number. For exam-ple, excessive production of thyroid hormone can increasethe synthesis of b adrenergic receptors in cardiac tissue,leading to some of the signs and symptoms of Graves’ dis-ease (see Chapter 42). Thus the number of cell-surfacereceptors, and thereby hormone sensitivity, can be con-tinuously regulated. This property of receptor biology canbe exploited therapeutically. For example, during the thirdtrimester of pregnancy, under the influence of nuclear hor-mones, the number of b2 adrenergic receptors on uterinesmooth muscle is dramatically increased, allowing the useof selective b2 adrenergic agonists, like terbutaline, to delaypremature labor (see Chapter 11).

FURTHER READING

Kenakin T: A pharmacology primer: Theory, applications, and meth-ods, 2 ed, San Diego, Academic Press; 2006.

For the latest information on receptor nomenclature, readers arereferred to the database maintained by the International Unionof Basic and Clinical Pharmacology at: http://www.iuphar-db.org/index.jsp.

SELF-ASSESSMENT QUESTIONS

1. Binding of a drug to a receptor generally:

A. Involves covalent binding between receptor and drug.

B. Involves more than one type of weak bond between drug and receptor.

C. Requires long-lasting stable bonds between drug and receptor.

D. Has a similar affinity for the several stereoisomers of the drug.

E. Is characterized by high KD values.

2. Long or continuous exposure of a receptor to an agent that is an antagonist can:

A. Result in a phenomenon called supersensitivity.

B. Desensitize the receptor.

C. Produce tachyphylaxis.

D. Cause down regulation of the receptor.

E. B and C are correct.

3. Which of the following is not a feature of receptors?

A. By acting on receptors, drugs can enhance, diminish, or block generation or transmission ofsignals.

B. The KD of drug binding to receptors is generally in the range of 1 to 100 mmol/L.

C. Specificity of drug binding to receptors is not absolute.

D. It may require more than one drug molecule to bind to a receptor and elicit a response.

E. Receptors are frequently glycosylated.

4. Hormone signaling can occur by:

A. Tyrosine phosphorylation.

B. Receptor association with G-proteins.

C. Formation of second messengers, such as cAMP.Continued


SELF-ASSESSMENT QUESTIONS, Cont’d

D. Mobilization of Ca++ from endoplasmic reticulum.

E. All are correct.

5. When added to an intestinal smooth muscle in a tissue bath, two different drugs both cause relax-ation of the muscle but with different EC50 values. Based on this information, which of the followingstatements is true?

A. The two drugs have similar chemical structures.

B. The two drugs have different potencies in causing relaxation.

C. Both drugs activate the same receptor in the muscle.

D. Both drugs are directly acting agonists.

E. The maximum relaxation caused by the two different drugs will be similar.

6. The affinity constant of a drug for a receptor (KD) is:

A. The concentration of drug that occupies half of the available receptor sites.

B. The ratio of the reverse to forward rate constants for the drug-receptor interaction.

C. Important in determining fractional occupancy of the receptor by the drug.

D. Characterized by all of the above.

E. Characterized by a and b only.


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