s. thomas abraham, michael l. adams

1135

Principles of Pharmacology and Medicinal ChemistryS. THOMAS ABRAHAM, MICHAEL L. ADAMS

58

I. INTRODUCTION. A complete understanding of the pharmacological actions of drugs requires an appreciation of their pharmacokinetic and pharmacodynamic properties, as well as the complexity of the biological responses modulated by these agents. This chapter will focus on the pharmacodynamic aspect of drugs with an emphasis on the mechanisms and consequences of drug–receptor interactions. Additionally, the chemical characteristics of pharmacological agents that influence their interactions with specific receptors will be addressed.

II. RECEPTORS. Currently, we understand that receptors are unique protein or glycoprotein structures that are responsible for the reception and transmission of information that ultimately alters the behavior of cells, organs, or even the entire organism. It is generally understood that endogenous hormones, neurotransmitters, or growth factors interact with specific receptors to modify cellular behavior.

A. Cell surface receptors and their signal transduction1. The seven transmembrane G protein–coupled receptors are localized in the plasma membranes

of cells in such a manner as to have seven transmembrane domains, with multiple extracellular and intracellular domains. This group of receptors is the most heterogeneous of the cell surface receptors and communicates with intracellular components by activating specific guanine nucle-otide-binding (G) protein intermediates.a. Gs-coupled receptors (e.g., b-adrenergic, vasopressin V2, glucagon, dopamine D1). These

receptors are functionally coupled to adenylyl cyclase, which catalyzes the conversion of ad-enosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), an intracellular sec-ond messenger (Figure 58-1). cAMP is responsible for the downstream activation of protein

Epi

ATPcAMP

PKA� receptor

Gs-protein

Adenylylcyclase

Figure 58-1. The cAMP-PKA signaling system is responsible for diverse biological effects such as increased heart rate/contractility, vasodilation, and neurotransmitter release. Epi, epinephrine; GS, guanine nucleotide-binding protein; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A.

1136 Chapter 58 II. A

kinase A (PKA), a multifunctional enzyme that alters the function of multiple substrates to ultimately produce effects such as increases in heart rate, release of glucose from the liver, decrease water loss in the kidneys, and increase neurotransmitter release.

b. Gq-coupled receptors (e.g., a1-adrenergic, muscarinic M1, angiotensin AT1). Binding of endogenous ligands such as norepinephrine or acetylcholine leads to conformational change in the relevant receptor and activation of the associated Gq protein, which in turn activates a membrane-bound phospholipase C. This enzyme catalyzes the hydrolysis of membranous phosphatidylinositol bisphosphate (PIP2) resulting in the production of inositol trisphos-phate (IP3) and diacylglycerol (DAG). The hydrophilic IP3 releases stored calcium from the sarcoplasmic reticulum, whereas DAG activates protein kinase C (Figure 58-2). These pro-cesses are eventually responsible for biological processes such as smooth muscle contraction, aldosterone release, salivary secretion, etc.

c. Gi/o-coupled receptors (e.g., muscarinic M2, a2-adrenergic, opioid). The best characterized results of activating receptors coupled to Gi/o proteins is the decrease in intracellular cAMP and opening of K1-channels leading to hyperpolarization. The overall response of these types of events is inhibitory and leads to responses such as decreasing heart rate and inhibition of neurotransmitter release.

2. Ion channels found on the membranes of excitable cells (cardiac muscle, nerve cells, etc.) are important regulators of cellular function and serve as targets for pharmacological intervention.a. Ligand-gated channels (e.g., nicotinic, GABAA, glutamate). The binding of endogenous

ligands (acetylcholine, GABA, etc.) on the extracellular domains allows the opening of ion-selective pores on the protein that allow for the movement of ions such as sodium, chloride, or calcium. Depending on the ion being conducted, the eventual physiological response may be skeletal muscle contraction, nerve depolarization, or hyperpolarization.

b. Voltage-gated channels (e.g., calcium, sodium, potassium channels). Depolarizing currents lead to opening of these channel proteins, allowing the selective movement of specific ions into (calcium, sodium) or out (potassium) of the cell. These ion fluxes lead to cell depolariza-tion (calcium, sodium) or repolarization (potassium) in a coordinated fashion to regulated muscle contraction and nerve action potential.

3. Growth factor receptors (e.g., epidermal growth factor [EGF] receptor, insulin receptor, fibro-blast growth factor receptor, interleukin-2 receptors). Generally, these receptors are composed of a single transmembrane domain containing a cytoplasmic tyrosine kinase. Thus, binding of EGF to its receptor results in receptor dimerization, activation of the tyrosine kinase motif, followed by cross phosphorylation of their cytoplasmic tail regions. This tyrosine phosphory-lation on specific sequences serves to produce src-homology binding domains for the dock-ing of additional proteins that transduce the signal to the interior of the cell. Consequently, EGF receptor activation leads to recruitment of Grb/Sos to the receptor with subsequent activa-tion of the extracellular signal-regulated kinase (ERK) pathway to promote cell growth/replica-tion (Figure 58-3). Similarly, insulin binding and receptor activation promotes insulin receptor substrate 1/2 (IRS-1/IRS-2) recruitment that increases plasma membrane glucose transporter expression and enhanced glucose uptake.

ACh

PIP2

PLC

IP3 + DAG

PKCCalciumrelease

M1 receptor

Gq-proteinFigure 58-2. The phosphoinositide signaling system is responsible for physiological responses such as salivary secretion, smooth muscle contraction, and hormone release. ACh, acetylcholine; Gq, guanine nucleotide-binding protein; PLC, phospholipase C; IP3, inositol trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; PIP2, phosphatidylinositol bisphosphate.

Principles of Pharmacology and Medicinal Chemistry 1137

4. Membrane transporters, pumps, and miscellaneous receptors (e.g., Na1/K1-ATPase, MDR-1 protein, natriuretic factor receptors). The natriuretic peptide family of proteins acti-vates membrane-bound, single-transmembrane domain receptors that contain cytoplasmic guanylyl cyclase activity. Membrane-bound pumps such as the Na/K-ATPase and the MDR-1/P- glycoprotein are also targets for various therapeutic interventions even though they do not have well-characterized endogenous ligands.

B. Intracellular receptors1. Cytoplasmic receptors may be as diverse as glucocorticoid hormone receptor, soluble guanylyl

cyclase, and other enzymes or proteins that serve as targets for drugs (e.g., HMG-CoA reductase, tubulin, or calcineurin). The steroid receptors in this group (e.g., glucocorticoid receptor) have cytoplasmic localization until complexed to corticosteroids at which time they are translocated to the nucleus to function as transcription factors for gene expression (Figure 58-4).

2. Nuclear receptors include those for thyroid hormone, sex steroids, retinoids, and peroxisome proliferator activator receptors. The binding of specific hormones to their respective receptors produces a complex that serves as transcription factors to modulate gene expression. Addition-ally, DNA and components of the nucleosome may serve as binding sites for specific drugs.

C. Microorganism proteins as drug targets. Various fungal, bacterial, and viral proteins (e.g., cell wall transamidase, fungal CYP450, viral thymidine kinase) are targeted for selective pharmacological intervention to treat relevant infections. These targets are often critical to the integrity or replication of the microorganism and their modulation can result in diminished viability of the infecting agent. Drug selectivity for these targets is achieved because they are structurally the distinction from analogous mammalian targets, and this often results in complete destruction of the offending microorganism.

III. DRUG–RECEPTOR INTERACTIONSA. Drug–receptor binding. At a fundamental level, drug molecules interact with specific receptors

in order to produce the ultimate pharmacological effect. This interaction may be governed by the formation of hydrogen, ionic, or van der Waals bonds between given drug–receptor pairs. In general,

ERK

MEK

Raf-1

EGF receptor

EGF

P

P

Figure 58-3. The ERK-MAPK signaling pathway mediates the biological processes of growth and differentiation. EGF, epidermal growth factor; MEK, ERK-kinase; ERK, extracellular signal-regulated kinase.

Gene transcription

Glucocorticoid R

Cortisol

Nucleus

Cytoplasm

Figure 58-4. Signaling by hormones such as cortisol occurs via a cytoplasmic receptor that promotes specific gene expression after binding the ligand.

1138 Chapter 58 III. A

these types of bonds are relatively weak and allow for the dissociation of the drug from the recep-tor, and the eventual pharmacological effect is reversed as the drug concentration at the receptor decreases. The tendency of drugs to bind to receptors is determined by its affinity for the receptor site as well as its concentration at that site, according to the law of mass action. Accordingly, the number of receptors [R] occupied by a drug depends on its concentration [D] and the drug–receptor associa-tion (k1) and dissociation (k2) rate constants such that

[D] 1 [R] k1

k2 [D 2 R] Equation 58-1

This equation suggests that the number of receptors bound by the drug at equilibrium is proportional to the concentration of the drug and is represented by a rectangular hyperbola (Figure 58-5). The ratio of k2 to k1 is better known as the dissociation constant (KD) and represents the concentration of drug required to occupy 50% of the receptor sites in a tissue (Figure 58-5). The inverse of the KD is equivalent to the affinity of a drug for its receptor and is proportional to the potency of the drug (below). Some drugs interact with their receptors by the formation of covalent bonds or dissociate so slowly from the receptor (very small k2) that the drug–receptor binding is irreversible or pseudo-irreversible at equilibrium. It could be expected that these types of drugs would have longer durations of action than those that are more rapidly reversible.

B. Drugs as agonists. Drugs that possess affinity for a specific receptor as well as intrinsic activity at that receptor are termed agonists. Agonists mimic the actions of the endogenous ligand (e.g., epinephrine for the b-adrenergic receptor) by modifying the conformation of the receptor in a manner that re-sults in the initiation of intracellular signaling events and a biological response. Thus, dobutamine is able to mimic the actions of epinephrine at the b-receptor, producing increases in rate and contractil-ity of the myocardium. For an agonist, Equation 58-1 can be modified to

[D] 1 [R] k1

k2 [D 2 R] N Response Equation 58-2

The consequence of drug–receptor complex formation is a biological response that is proportional to the number of complexes formed. The application of increasing doses of an agonist will produce increasing biological response until a maximum effect is achieved. This relationship is represented by a sigmoidal dose–response curve when drug dose is plotted on a logarithmic scale (Figure 58-6).1. Full agonists are able to produce increasing biological response with increasing dose until a maxi-

mal effect or efficacy (Emax) is achieved, represented by a dose–response relationship (Figure 58-6). From this relationship, the effective dose that produces 50% of the Emax (ED50) can be determined as shown in Figure 58-6. The ED50 is a measure of the potency of the agonist such that drug A is more potent than drug C, even though the two have similar Emaxs. Epinephrine is a full agonist at the b-receptor.

100 Bmax

KD

80

60

40

20

0

Drug concentration

Dru

g bi

ndin

g(p

mol

/mg

prot

ein)

Figure 58-5. The binding of a drug to its receptor follows a rectangular hyperbolic relationship where the KD is the concentration at which half the receptors are occupied. The Bmax is the maximum number of binding sites (receptors) available to the drug and may be expressed in units such moles/gram tissue.


2. Partial agonists possess reduced intrinsic activity or efficacy, which results in reduced Emax rela-tive to a full agonist (drug B versus drug A or C, Figure 58-6). However, a partial agonist may have greater affinity for the receptor, resulting in greater potency than a full agonist (compare drug B and C, Figure 58-6). Oxymetazoline (Afrin®) and buprenorphine (Buprenex®) are partial agonists at the a-adrenergic and m-opioid receptors, respectively.

C. Drugs as antagonists. Drugs with affinity for a receptor but lacking intrinsic activity are called antagonists. These drugs are unable to alter receptor conformation in a way that leads to initia-tion of intracellular signal transduction processes and have their predominant pharmacological action by preventing the binding and actions of an endogenous ligand. Thus, atropine binds to the muscarinic receptor with high affinity but is unable to initiate a biological response; on the other hand, by occupying the binding site, it prevents the ability of acetylcholine to bind and produce an effect.1. Equilibrium-competitive antagonists reversibly interact with the same binding site on the re-

ceptor as the agonist to prevent agonist binding and activation of the receptor. The reversibility of antagonist binding (Equation 58-1) allows the increasing doses of agonist to displace the an-tagonist to eventually produce the maximal biological response but with an apparent decrease in the affinity (increased ED50). On an agonist dose–response curve, the effect of equilibrium- competitive antagonists would be to shift the agonist curve to the right without a change in the maximal response (Figure 58-7A). Atropine is an example of an equilibrium-competitive antago-nist at the muscarinic receptor.

ED50A ED50C

100

50

0

Log drug dose

A

B

C

Perc

ent m

axim

um re

spon

se

Figure 58-6. For the dose–response curves of three agonists, it can be seen that the A and C can be classified as full agonists because they are able to produce the maximal response possible, whereas B has a lower maximum, indicating a lower efficacy. However, agonist B has a greater potency than drug C because its ED50 is lower than that of C. ED50A: dose of A producing 50% of its maximal response.

ED50 ED50�

Emax�

Emax100

+ Antagonist

+ Antagonist

50

0

Log agonist dose

Perc

ent r

espo

nse

ED50

100

50

0

Log agonist dose

Perc

ent r

espo

nse

A B

Figure 58-7. A. The apparent decrease in agonist potency (increase in the ED50 to ED509; dashed line) in the presence of the antagonist without a decrease in the maximal response is indicative of an equilibrium-competitive antagonist. B. The decrease in the maximal response of the agonist curve after antagonist treatment (dashed line) would suggest the actions of a nonequilibrium or irreversible antagonist.

1140 Chapter 58 III. C

2. Nonequilibrium-competitive antagonists interact with their receptors in an irreversible or pseudo-irreversible manner, resulting in a very small k2 (Equation 58-1). This irreversibility (usually due to covalent bonding) would reduce the number of receptors available to produce a biological response, which results in an agonist dose–response curve with reduced Emax and variable effect on potency (Figure 58-7B). Phenoxybenzamine (Dibenzyline®) is an example of nonequilibrium-competitive antagonist at the a-adrenergic receptor.

3. Inverse agonists/antagonists reduce the basal coupling of the receptor to the intracellular signal transduction processes, producing a negative pharmacological effect even in the absence of recep-tor agonists. b-Blockers like propranolol (Inderal®) are examples of drugs with both equilibrium-competitive antagonist and inverse agonist activity.

4. Noncompetitive antagonists interact with a distinct site to that occupied by the agonist to pre-vent the biological response initiated by the agonist. This distinct site may be on the receptor itself (tyrosine kinase domain of the EGF receptor) or a downstream signaling molecule from the receptor (calcineurin in T-cell receptor signaling). The binding of the antagonist for its site cannot be displaced by increasing doses of agonist because there is no overlap in the two sites—there is no competition between the two ligands for a common site. Thus, erlotinib (Tarceva®) is a non-competitive antagonist of EGF at the EGF receptor and would reduce the efficacy of the agonist (Emax) to stimulate cell growth.

D. Enzymes as drug receptors. In many instances, cellular enzymes behave similarly to classical recep-tors in their interaction with drug molecules via ionic, hydrogen, van der Waal’s, or covalent bonding. However, important differences in the behavior of enzymes warrant separate treatment.1. Competitive enzyme inhibitors are drugs that bind to the active site of an enzyme in a man-

ner that prevents substrate binding and conversion to a product. Analogous to classical drug– receptor interactions, these inhibitors would be considered competitive regardless of whether drug binding was reversible or irreversible. The inhibition of HMG-CoA reductase by simvastatin ( Zocor®) would be considered competitive with respect to the substrate HMG-CoA.a. Transition-state inhibitors mimic the transition state of the enzyme substrate having the

highest free energy of activation and thus a high binding affinity for the substrate/active site (e.g., captopril [Capoten®] for the angiotensin-converting enzyme).

b. Suicide enzyme inhibitors are drugs that are catalyzed or destroyed in the process of binding to the active enzyme site; for example, neostigmine (Prostigmin®) is metabolized to a carba-mate intermediate that covalently binds to the active site of acetylcholinesterase.

2. Allosteric modulators bind to a distinct site from that of the substrate and thereby alter enzyme activity. Theoretically, this type of modulation can increase or decrease enzyme activity and not automatically be classified as inhibition. Allosteric modulators that inhibit enzyme activity may be considered noncompetitive inhibitors; for example, efavirenz (Sustiva®) inhibits the polymerase function of HIV reverse transcriptase.

E. Modulation of receptor sensitivity1. Desensitization of seven transmembrane-spanning receptors generally occurs with sustained

stimulation of the receptor and occurs due to reduced coupling to G proteins. Uncoupling of the receptor is due to phosphorylation of the receptor, which prevents its interaction with the G protein and also reduces the affinity of the agonist for the receptor. Myocardial b-receptors in patients with heart failure are thought to be desensitized due to sustained sympathetic nervous system stimulation.

2. Downregulation of the receptor is the result of prolonged receptor stimulation that leads to incorporation of the receptor into clathrin-coated pits and removal of the receptor from the plasma membrane. This process reduces agonist signaling to the intracellular compartment. Ultimately, the receptor may be transported to the lysosomal compartment for destruction or recycled back to the plasma membrane to restore cell signaling. The sustained use of b-agonists like albuterol (Ventolin®) causes the downregulation of b2-receptors in asthmatic patients.

3. Receptor hypersensitivity/supersensitivity is exhibited by increased response to agonist stimu-lation and is most likely due to increased receptor number or enhanced coupling of the recep-tor to intracellular signaling processes. This phenomenon usually occurs with chronic reduction in receptor stimulation due to diminished endogenous agonists (e.g., after autonomic or motor nerve destruction). Reversal of prolonged antagonist therapy has also been associated with recep-tor supersensitivity (e.g., abrupt withdrawal of b-blocker therapy).


IV. PHARMACODYNAMICS IN THE CLINICAL POPULATION. Pharmaco-logical therapy in the human patient population is fundamentally based on the principles of dose–response relationships, with higher doses producing greater effects until a maximum is reached. An inherent assumption of the dose dependency of a drug effect is that it is mediated through a specific receptor, regardless of whether the drug is an agonist or antagonist. However, the relative potencies of drugs (as indicated by the ED50s) may not reflect the affinity of the drug for its receptor because this value can also be influenced by several pharmacokinetic parameters; that is, a high-affinity drug may exhibit a greater ED50 than a low-affinity drug if the former is poorly absorbed or more quickly inactivated by hepatic systems.

A. Quantal dose–response relationship may be developed in a patient population based on the dose required to produce a specific outcome; for example, the dose required to cause sleep or produce a 10% decrease in blood pressure. This would result in some individuals requiring very small doses, whereas others would need much higher amounts to induce the effect, the overall response following a Gaussian or normal distribution (Figure 58-8A). The mean of this distribution would be equivalent to the ED50 and 95% of patients would respond to a dose that is 2 standard deviations above or below the ED50 (indicated by the range shown in Figure 58-8A). Plotting the same data as the administered dose versus the cumulative number of patients producing the effect exhibits the recognizable dose–response curve (Figure 58-8B).

B. Graded dose–response relationship may be seen in a patient population or individuals where increasing doses of a drug results in greater pharmacological effect. This is best demonstrated by drugs that can be titrated to produce a desired outcome; for example, 10, 20, 40, and 80 mg of ator-vastatin (Lipitor®) can produce 33%, 38%, 45%, and 53% lowering in LDL cholesterol, respectively (see Figure 10-17).

C. Dose-dependent drug toxicity can also result in the course of pharmacological therapy and follows a similar normal distribution as demonstrated in Figure 58-8A—only these effects usually occur at higher doses (e.g., 1% of the population may show toxicity to the same drug at 6 mg/kg). Plotting graded dose–response curves for the therapeutic and toxic effects of drug may produce relationships as seen in Figure 58-9. From the graph, it can be seen that the dose-producing toxicity in 50% of the population (TD50) is larger than the ED50; however, the TD1 is much closer to the ED99 and is an indication of the margin of safety of the drug. If the toxic effect being measured is death, then the lethal dose producing 50% death in the population is called the LD50, and the ratio of the LD50 to the ED50 is called the therapeutic index. Drugs with a low margin of safety are likely to show toxicity at doses that are in the therapeutic range (e.g., warfarin [Coumadin®] and digoxin [Lanoxin®]).

ED50

ED50

15

10

5

01 2 3 4 5 1 2 3 4 5

Dose (mg/kg)

Perc

ent r

espo

ndin

g

ED50

100

50

0

Dose (mg/kg)

Cum

ulat

ive

resp

onse

A B

Figure 58-8. A. The percentage of patients in a population that respond to a pharmacological intervention can be represented by a Gaussian distribution where some require only 1 mg and others need as much as 5 mg of the drug to show the desired response. This in effect is the dose–response relationship of the entire population as demonstrated by the graph (B) where plotting the cumulative number of responders after each dose gives the classic dose–response curve. In either graph, the dose producing an effect in 50% of the population (ED50) can be determined as shown.

1142 Chapter 58 V. A

V. STRUCTURAL DETERMINANTS OF DRUG ACTIONA. Structural specificity is conferred by physical and chemical characteristics, or physicochemical

properties, of drugs that allow for specific binding and modulation of the target receptor. These physicochemical properties of a drug are influenced by the acid–base character, water solubility, and stereochemistry, which are dependent on the chemical structure. The physicochemical properties are also important for absorption, distribution, metabolism, and excretion. This structure-to-function connection is the basis for structure–activity relationships (SARs) that are defined by changing the chemical structure and determining its influence on biological activity.

B. Pharmacophore is a term used to describe the critical organic functional groups and their spatial relationship within a drug molecule required for a specific pharmacological activity. Drugs with simi-lar structure and the same pharmacophore typically have similar pharmacological activity but may have other ADME characteristics or potencies that distinguish them from one another.

C. A functional group is a specific group of atoms that have a distinctive acid–base character, contribu-tion to water solubility, and chemical reactivity. The combination of multiple functional groups can influence the properties of adjacent functional groups and together define the physicochemical prop-erties of the drug molecule. Common functional groups are shown in Tables 58-1, 58-2, and 58-3.

D. A bioisostere is a compound containing an atom or group of atoms that is spatially and electronically sim-ilar to another molecule that produces a similar biological activity. The goal of bioisosteric replacement is frequently to increase potency, decrease side effects, separate biological activities, or increase the duration of action by altering metabolism. Additionally, bioisosteric substitutions may result in a compound that is an antagonist or inhibitor of the parent molecule; for example, allopurinol (Zyloprim®) inhibits xanthine oxidase, which, through a multistep metabolic process, converts hypoxanthine to uric acid (Figure 58-10).

E. The stereochemistry of a drug molecule also contributes to the structural specificity of a drug by defining the three-dimensional spatial arrangement of the functional groups required for receptor interactions. Stereoisomers have the same atoms and connectivity but different arrangements in space. Stereoisomers can be divided into three main groups: enantiomers; diastereomers, including geometric isomers; and conformational isomers.1. Enantiomers are nonsuperimposable mirror images of each other because they contain at least

one asymmetric, or chiral, center, usually a carbon covalently bound to four different substituents. A drug containing one chiral carbon can exist in one of two nonsuperimposable isomeric forms, although a drug with multiple chiral centers (n) has the potential to exist in one of 2n isomeric forms that are enantiomers or diastereomers (Figure 58-11).a. Enantiomers have identical physical and chemical properties except for the direction of rotation

of plane-polarized light measured in a polarimeter. One isomer will rotate plane-polarized light in a clockwise direction (dextrorotatory; d or 1) and the other in a counterclockwise direction (levorotatory; l or 2).

b. An equal molar mixture of a pair of enantiomers (1 and 2) is called a racemic mixture or racemate. A racemate has a net zero rotation of plane-polarized light and is therefore optically inactive. Currently, some active drugs are marketed both as a racemate (cetirizine [Zyrtec®]) and as an enantiomerically pure product (levocetirizine [Xyzal®]) (Figure 58-11).

ED50

ED99

Therapeuticeffect

Toxiceffect

TD50TD1

100

50

0

Log dose

Perc

ent r

espo

nse

Figure 58-9. Drugs can have toxic or undesirable effects that follow a dose–response relationship; however, these effects often require higher doses to be observe and thus their graph appears shifted to the right of the therapeutic effect (graph on the right). TD1: dose producing a toxic response in 1% of the population.


Table 58-1 NEUTRAL FUNCTIONAL GROUPS

Group Structure Group Structure

AlkaneCH3

H3C

CH2

CH2Ketone

CH3

O

CH3C

Alkene

H3C

H CH3

H

CC Amine (quaternary)

H3CH2C

H3CH2C + CH2CH3

CH2CH3

N

Aromatic Ester OCH2CH3

CH3CH2COOCH2CH3

or

O

CH3CH2C

Alcohol (primary)

OHH3C AmideNHCH2CH3

O

CH3CH2C

Alcohol (secondary)

OHHC

CH3

H3CCarbonate

OCH2CH3

O

CH3CH2CO

Alcohol (tertiary)

OHC

CH3

CH3

H3C CarbamateNHCH2CH3

O

CH3CH2CO

Ether H3CH2C CH2CH3

OUrea

NHCH2CH3

O

CH3CH2CHN

Thioether H3CH2C CH2CH3

SNitro

H3CH2C

+

–

Oor NO2

O

H3CH2C N

AldehydeH

O

CH3CNitrate NO2OH3CH2C

c. Enantiomers can have large differences in potency, receptor fit, biological activity, transport, and metabolism. These differences result when the drug molecule has an asymmetric interaction with a receptor, a transport protein, or a metabolizing enzyme. The enantiomer with the desired pharmacological effect is called the eutomer, whereas the other isomer is the distomer. The distomer may not have pharmacologic activity or may be responsible for adverse effects.

d. Enantiomers are distinguishable in a chiral environment, including the human body, or by determining the rotation of plane-polarized light in a polarimeter. These are properties of the molecule but they do not reveal information concerning the absolute configuration around the chiral center. To determine the absolute configuration, the Cahn-Ingold-Prelog (CIP) system for assigning priority is used (R or S designation). It is important to remember that the CIP absolute configuration is applied to each chiral center and is independent of the direction of rotation of plane-polarized light for the molecule as a whole. In a pair of enantiomers, all stereocenters are opposite in their absolute configuration and therefore also in their CIP designation.

2. Diastereomers are stereoisomers that are not enantiomers. More specifically, they are stereoiso-mers that are not mirror images of each other or superimposable.a. Like enantiomers, diastereomers can be optically active. But diastereomers have some stereocen-

ters that are identical and some that are opposite in their absolute configuration. Diastereomers

Table 58-2 ACIDIC FUNCTIONAL GROUPS

Group Structure

Carboxylic acid OH

CH3CH2COOHor

O

CH3CH2C

ImideO O

CHN CH3C CH3

Phenol

OH

Sulfonamide

O

O

SH3CH2C NHCH2CH3

Sulfonic acid

O

O

SH3CH2C OH

Sulfonimide CH3

O

O

S

O

CH3CHN

Tetrazole

N

N

N

HN

CH3

Thiol SHH3CH2C

Table 58-3 BASIC FUNCTIONAL GROUPS

Group Structure

Amine (primary) NH2H3CH2C

Amine (secondary) NH

H3CH2C

H3CH2C

Amine (tertiary) N CH2CH3

H3CH2C

H3CH2C

Amine (aromatic)N

Imine NHH3CHC

AmidineC

NH

H3CH2C NH2

Guanidine

C

N

H3CH2C NH2

H3CH2C

1144


H2N

NH

N

CH2CH3

Procainamide

CH2CH3

O

NH

Allopurinol

N

N

N

OH

H2N

ON

CH2CH3

Procaine

CH2CH3

O

NH

Hypoxanthine

N

N

N

OH

Figure 58-10. Bioisosteric pairs procainamide/procaine and allopurinol/hypoxanthine. The isosteric replacements are boxed.

possess different physicochemical properties and thus differ in properties such as solubility, volatil-ity, and melting point. For optically active diastereomers, two or more stereocenters are required.

b. Epimers are a special type of diastereomers because epimers are structurally identical in all respect except for the stereochemistry of one chiral center. The process of epimerization (in which the stereochemistry of one chiral center is inverted) is important in drug degradation and inactivation (Figure 58-12).

c. Geometric isomers are diastereomers because they are not mirror images and they have different physicochemical properties and pharmacologic activity (Figure 58-13). Geometric isomers are also called cis–trans isomers and result from restricted rotation around a chemi-cal bond. This can be an alkene (double bond) or a fused ring system within a molecule that prevents interconversion between the two isomers.

3. Conformational isomers, also known as rotamers or conformers, are nonsuperimposable orien-tations of a molecule that results from the free rotation of atoms around a single bond. Almost every drug can exist in more than one conformation, and this ability allows many drugs to bind to multiple receptors and receptor subtypes. For example, the trans conformation of acetylcholine binds to the muscarinic receptor, whereas the gauche conformation of acetylcholine binds to the nicotinic receptor (Figure 58-14). It should be noted that conformational isomers are chemically indistinguishable (i.e., they have all the same physicochemical properties) from each other be-cause the only difference between the conformers is the free rotation around a bond.

(+)-(S)-Cetirizine

Cl

O

H

N

NO

OH

(–)-(R)-Cetirizine (Xyzal)

(+/–)-Cetirizine (Zyrtec)

Cl

O

H

N

NO

OH

Figure 58-11. The two enantiomers of cetirizine. The chiral, or asymmetric, carbon is bonded to four different groups: a piperazine ring, a chlorinated benzene ring, an unsubstituted benzene, and a hydrogen. The structures shown are mirror images, which cannot be superimposed. A racemic mixture of cetirizine is marketed as Zyrtec, whereas the enantiomerically pure levocetirizine is marketed as Xyzal.

1146 Chapter 58 VI. A

Figure 58-12. Epimerization of tetracycline to 4-epitetracycline. The stereochemistry of the 4-dimethylamino group is inverted; however, the stereochemistry of all other chiral centers remains unchanged.

Figure 58-13. The presence of the double bond in diethylstilbestrol allows for the formation of cis and trans geometric isomers. The functional groups of these isomers are separated by different distances; they generally do not fit the same receptor equally well. As a result, the trans isomer has estrogenic activity and the cis isomer only has 7% the estrogenic activity of the trans isomer.

VI. PHYSIOCHEMICAL DETERMINANTS OF DRUG ACTION. The polarity and acid–base property of a drug are two primary physiochemical characteristics of drugs.

A. Polarity of drugs is a measure of their lipid and water solubility and is generally expressed as the partition coefficient.1. Partition coefficient (P) of a drug is the ratio of the solubility of the agent in an organic lipophilic

solvent (usually n-octanol) to its solubility in water or aqueous buffer.

P 5 [Drug]organic _ [Drug]water

The partition coefficient is often expressed as the logarithmic value, log P.2. Water solubility or hydrophilicity of a drug is dependent on two major factors: its ionic and

hydrogen-bonding capacity. The presence of oxygen- and nitrogen-containing functional groups generally enhances water solubility, which is required fora. drug dissolution in the gastrointestinal (GI) tract,b. preparation of parenteral drug solutions, andc. ophthalmic drug solutions.

3. Lipid solubility or lipophilicity is increased by the presence of nonionizable functional groups (hydrocarbon chains or ring systems) and is important ina. drug absorption from the GI tract,b. penetration of drug through biological membranes (e.g., cell membranes, blood–brain barrier),c. preparation of intramuscular depot injectable formulations,d. drug absorption via the pulmonary route,e. increased potency of topically applied formulations, andf. increased plasma protein binding.


Figure 58-14. The trans (A) and gauche (B) conformations of acetylcholine occur as the result of rotation around the carbon–carbon single bond.

B:H�

[H�][A�][AH]Ka or�

pKa �log� Ka log�

H�B: �

A-H H�A� �

[H�][B:][BH�]Ka �

1Ka

Figure 58-15. The ionization constant (Ka) and the pKa indicate the equilibrium between the protonated species, the unprotonated species, and the strength of the acid or base.

B. Acid–base characteristic of drugs influence their ionization in biological fluids. Using the Brønsted– Lowry definition, acids donate a proton to become ionized, whereas bases accept a proton to become ionized.1. The ionization constant (Ka) indicates the relative strength of the acid or base by indicating the

ratio of the unprotonated species to the protonated species (Figure 58-15). An acid with a Ka of 1 3 1023 is stronger (more ionized [A2] species) than an acid with a Ka of 1 3 1025, whereas a base with a Ka of 1 3 1027 is weaker (less ionized [BH1] species) than a base with a Ka of 1 3 1029.

2. The ionization constant is more commonly reported as the pKa or the negative log of the ioniza-tion constant. The pKa also indicates the relative strength of the acid or base. Using the aforemen-tioned examples, an acid with a Ka of 1 3 1023 has a pKa of 3 and is stronger than an acid with a Ka of 1 3 1025 (pKa of 5), whereas a base with a Ka of 1 3 1027 (pKa of 7) is weaker than a base with a Ka of 1 3 1029 (pKa of 9).

3. Acids can be described as strong or weak acids based on their ability to donate a proton.a. Strong acids are completely ionized when placed in water. Strong acids include hydrochloric

acid (HCl), sulfuric acid (H2SO4), nitric acid (HNO3), hydrobromic acid (HBr), iodic acid (HIO3), and perchloric acid (HClO4).

b. Weak acids are partially ionized when placed in water. Most organic acids contained in drugs are weak acids. The following functional groups are weak acids. The approximate pKa range is shown in parentheses (see Table 58.2). (1) Carboxylic acid group (MCOOH with a pKa range of 4–6)(2) Phenolic group (ArMOH with a pKa range of 9–11)(3) Sulfonic acid group (MSO3H with a pKa range of 0–1)(4) Sulfonamide group (MSO2NH2 with a pKa range of 9–10)(5) N-Aryl sulfonamide group (MSO2NHMAr with a pKa range of 6–7)(6) Imide group (MCOMNHMCOM with a pKa range of 9–10)(7) Thiol (RMSH with a pKa range of 9–11)(8) Sulfonimide (MSO2NHMCOM with a pKa range of 5–6)(9) Tetrazole (five-member ring CHN4 with a pKa range of 4–6)

c. When a weak acid, like acetic acid (pKa 5 4.76), is placed in an acid medium (high [H1], low pH), the equilibrium shifts to the left and suppresses ionization. This decrease in ionization conforms to Le Chatelier’s principle, which states that when a stress is placed on an equilibrium reaction, the

1148 Chapter 58 VI. B

reaction will move in the direction that tends to relieve the stress. When the same weak acid is placed in an alkaline medium (very low [H1], high pH), the ionization increases producing more H1.

CH3COOH D CH3COO2 1 H1

d. Weakly acidic drugs are less ionized in acid media than in alkaline media. When the pKa of an acidic drug is greater than the pH of the medium in which it exists, it will be . 50% in its nonionized form and thus more likely to cross lipid cellular membranes.

4. Bases can be described as strong or weak bases based on their ability to accept a proton.a. Strong bases are completely ionized when placed in water. Strong bases include sodium

hydroxide (NaOH), potassium hydroxide (KOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), barium hydroxide (Ba(OH)2), and quaternary ammonium hydroxides.

b. Weak bases are partially ionized when placed in water. Most organic bases contained in drugs are weak bases. The following functional groups are weak bases. The approximate pKa range is shown in parentheses (see Table 58.3). (1) Primary, secondary, and tertiary aliphatic amines (R-NH2, R2MNH, and R3MN,

respectively, with a pKa range of 9–11)(2) Aromatic amine (aromatic ring with N included in ring with a pKa range of 5–6)(3) Arylamine (ArMNH2 with a pKa range of 4–5)(4) Imine (MCHBNH with a pKa range of 3–4)(5) Amidine (MNHMCBNM with a pKa range of 10–11)(6) Guanidine (MNHMCBNH(NH2) with a pKa range of 12–13)

c. When a weak base like ethylamine (pKa 5 10.7) is placed in an acid medium (high [H1], low pH), the equilibrium shifts to the left and increases the ionization (see Le Chatelier’s principle in section VI.B.3.c). When the same weak base is placed in an alkaline medium (very low [H1], high pH), the ionization decreases.

CH3CH2NH31 D CH3CH2NH2 1 H1

d. Weakly basic drugs are less ionized in alkaline media than in acid media. When the pKa of a basic drug is less than the pH of the medium in which it exists, it will be . 50% in its nonion-ized form and thus more likely to cross lipid cellular membranes.

5. Percent ionization can be approximated by using the rule of nines. If the |pH 2 pKa| 5 1, then a 90:10 ratio (one nine in the ratio) exists. If the |pH 2 pKa| 5 2, the ratio becomes 99:1 (two nines in the ratio), and if the |pH 2 pKa| 5 3, the ratio becomes 99.9:0.1 (three nines in the ratio). The predominant form, ionized or unionized, in these ratios can be easily determined.

6. Drug salts are made by the combination of an acid and a base. Because most drugs are organic molecules, drug salts can be divided into two classes based on the chemical nature of the sub-stance forming the salt.a. Inorganic salts are made by combining drug molecules (a weak base or acid) with strong

inorganic acids or bases such as hydrochloric acid, sulfuric acid, potassium hydroxide, or so-dium hydroxide. The salt form of the drug made from a strong inorganic and a weak organic generally has increased water solubility in comparison with the parent molecule and increased aqueous dissolution.

b. Organic salts are made by combining drug molecules with either small hydrophilic organic compounds (e.g., succinic acid, citric acid) or lipophilic organic compounds (e.g., procaine). Water-soluble organic salts are used to increase dissolution and bioavailability as well as to aid in the preparation of parenteral and ophthalmic formulations. Lipid-soluble organic salts are primarily used to make depot injections.

c. Dissolution of salts can alter the pH of an aqueous medium.(1) Salts of strong acids (e.g., HCl, H2SO4) and basic drugs dissociate in an aqueous medium

to yield an acidic solution.(2) Salts of strong bases (e.g., NaOH, KOH) and acidic drugs dissociate in an aqueous

medium to yield a basic solution.(3) Salts of weak acids and weak bases dissociate in an aqueous medium to yield an acidic,

basic, or neutral solution, depending on the respective ionization constants involved.


(4) Salts of strong acids and strong bases (e.g., NaCl) do not significantly alter the pH of an aqueous medium.

7. Amphoteric drugs contain both acidic and basic functional groups and are capable of forming internal salts, or zwitterions, which often have dissolution problems because the ions interact with each other and not the aqueous environment.

8. A neutralization reaction might occur when an acidic solution of an organic salt (a solution of a salt of a strong acid and a weak base) is mixed with a basic solution (a solution of a salt of a weak acid and a strong base). The nonionized organic acid or the nonionized organic base is likely to precipitate in this case. The reaction is the basis for many drug incompatibilities, particularly when intravenous solutions are mixed.

VII. NONCLASSICAL ACTIONS OF DRUGS. Some pharmacological agents appear to produce their therapeutic effects without interacting with a specific receptor protein, in a manner described by canonical drug–receptor characteristics. The following list is not exhaustive and may change as research explains previous “nonspecific” mechanisms; for example, inhalational anesthetics (e.g., halothane) have been shown to have specific interactions with and modulation of GABAA receptors.

A. Interaction with membranes1. Polyene antifungal agents (e.g., amphotericin B [Ambisome®]) interact with fungal membrane

sterols to cause pore formation and cell lysis.2. Alcohols, solvents (e.g., ethanol, isopropyl alcohol, phenol, chlorhexidine) dissolve bacterial

membranes to produce cell lysis.3. Certain antibiotics (e.g., polymyxin B) interact with phospholipid components of bacterial

membranes to cause cell lysis.B. Interaction with cytoskeletal components. Microtubule disruptors (e.g., vincristine [Vincasar®],

paclitaxel [Taxol®]) interact with tubulin filaments to interfere with their role in mediating cell division.C. Interaction with DNA/RNA

1. Alkylating agents (e.g., nitrosoureas, nitrogen mustards) react with components such as the pyrimidine and purine bases causing cross-linking of DNA strands.

2. DNA-intercalating agents (e.g., actinomycin D [Dactinomycin®]) interact with adjacent G-C bases and the minor groove of the DNA double helix.

3. DNA-cleaving agents (e.g., bleomycin [Blenoxane®]) bind to DNA causing localized oxidative stress and DNA strand breaks.

D. Neutralizing reactions1. Acid–base interactions (e.g., aluminum sulfate, calcium carbonate) react with peptic HCl to re-

duce symptoms of dyspepsia. The inactivation of heparin by protamine sulfate is another example of this type of neutralization.

2. Chelators (e.g., EDTA, dimercaprol) bind metal ions such as Ca21, Pb21, and Hg21 with high affinity and enhance their removal from the body.

3. Antibody–antigen complexes (e.g., antivenoms, antidigoxin antibodies [Digibind®]) are admin-istered to rapidly decrease systemic toxins or drugs via the immune system.

VIII. MAJOR SOURCES OF COMMERCIALLY VIABLE DRUGSA. Naturally occurring drugs are usually obtained from plant or animal sources.

1. Alkaloids are nitrogen-containing compounds occurring in plants and possessing pharmacologi-cal activity. Most alkaloids have a basic character (e.g., morphine from opium poppy or atropine from belladonna), whereas others are neutral amides (e.g., colchicines from autumn crocus). All alkaloids end in the suffix –ine; however, not all drugs that end with this suffix are alkaloids (e.g., nifedipine [Procardia®] or meperidine [Demerol®]).

2. Hormones are endogenous chemicals released into the blood by a tissue or organ to act on more distant tissues or organs. These may be biogenic amines, peptides/proteins, or steroids.a. Biogenic amines such as epinephrine are released by the adrenal medulla to alter the function

of multiple organ systems during sympathetic activation.b. Steroids such as testosterone, estradiol, cortisol, etc. are chemical derivatives of cyclopen-

tanoperhydrophenanthrene and often obtained from animal or human sources.

1150 Chapter 58 VIII. A

c. Peptides/proteins such as insulin, glucagon, and somatostatin are obtained from animal sources or recombinant DNA technology. Generally, peptide and protein drugs have limited oral activity and have to be administered parenterally.

3. Glycosides are drugs that contain a sugar moiety bound to a nonsugar or aglycone portion via glycosidic bonds and are most often from plant (e.g., digoxin) or microbial (e.g., streptomycin, doxorubicin) sources.

4. Polysaccharides are drugs composed of sugar polymers from human or animal sources (e.g., heparin, enoxaparin). Structural modification of naturally occurring sugars can yield additional drugs (e.g., sucralfate [Carafate®]).

5. Antibiotics are often fungal or other microbial products that have suppressive or lethal effects on other microorganisms (e.g., penicillin, tetracycline).

6. Vitamins are plant and animal products that function as essential cofactors for various meta-bolic processes in the body. Water-soluble vitamins include thiamine (B1), riboflavin (B2), niacin (B3), pyridoxine (B6), cyanocobalamin (B12), ascorbic acid (C), folic acid, pantothenic acid, and biotin (H). Fat-soluble vitamins include a-tocopherol (E), ergocalciferol (D), retinol (A), and phytonadione (K).

B. Synthetic products1. Small organic molecules produced by organic synthesis to mimic the activity of naturally occur-

ring chemicals or found to have unique pharmacological activity not previously identified.a. Antimicrobials (e.g., ciprofloxacin [Cipro®] or trimethoprim) are man-made chemicals that

inhibit unique microbial targets such as the DNA gyrase or dihydrofolate reductase to treat susceptible infections.

b. Receptor ligands compose the largest group of drugs and often mimic endogenous receptor ligands; for example, propranolol (Inderal®) has structural homology to epinephrine; meperi-dine (Demerol) mimics the structural features of endorphins at the m-opiate receptors.

c. Enzyme inhibitors may be targeted against microbial proteins as in section VIII.B.1.a above or mammalian enzymes; for example, aliskiren (Tekturna®) against renin, pravastatin ( Pravachol®) against hepatic HMG-CoA reductase, or imatinib (Gleevec®) against c-kit tyrosine kinase.

2. Peptides/proteinsa. Peptides. Eptifibatide (Integrilin®) is a synthetic cyclic peptide that mimics components of

carpet viper venom to prevent platelet aggregation.b. Proteins. Lepirudin (Refludan®) is a recombinant, synthetic derivate of hirudin, the anticoagu-

lant from leeches.3. Polysaccharides. The synthetic pentasaccharide fondaparinux (Arixtra®) mimics the portions of

heparins that interact with coagulant proteins.

Study Questions

Directions: Each of the questions, statements, or incomplete statements in this section can be correctly answered or completed by one of the suggested answers or phrases. Choose the best answer.

1. All of the following are examples of specific receptors for drug action except(A) stomach acid.(B) membrane proteins.(C) cytoplasmic proteins.(D) nuclear proteins.(E) DNA.

2. A 40-year-old teacher was prescribed lovastatin for the treatment of hypercholesterolemia. She wanted to know the mechanism of the drug before taking it. Her pharmacist explained to her that lovastatin acts by blocking the substrate-binding site of the enzyme b-hydroxy-b-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes the rate-limiting step in cholesterol biosynthesis. Such drug effect is known as(A) addition.(B) synergism.(C) noncompetitive antagonism.(D) potentiation.(E) competitive antagonism.


3. A 70-year-old man had prolonged bleeding during an elective knee surgery. Subsequently, the patient admitted to the surgeon that he had been self-administering 81 mg aspirin daily. The consultant pharmacist explained to the patient that, although aspirin has a short plasma half-life, it can irreversibly inhibit platelet function by acetylating the nonsubstrate-binding site of the platelet cyclooxygenase, resulting in prolonged effect on platelet aggregation. This drug effect is known as(A) potentiation.(B) competitive antagonism.(C) synergism.(D) addition.(E) noncompetitive antagonism.

4. A 65-year-old woman with intractable pain secondary to bony metastasis of breast cancer had been receiving escalating doses of morphine sulfate intravenously. At 10 a.m., she was found to be unresponsive, her respiratory rate was 4 breaths per minute, and her pupils were pinpointed. Naloxone (Narcan), a competitive antagonist of the opiate receptor, was given intravenously and repeated once. She gradually became conscious and began to complain of pain unrelieved by morphine given at the previous dose. This is most likely because(A) naloxone directly aggravates the pain caused by

the bony metastasis.(B) naloxone reduces the Emax for morphine.(C) naloxone reduces the ED50 for morphine.(D) naloxone increases the Emax for morphine.(E) naloxone increases the ED50 for morphine.

5. Which of the following statements regarding signal transduction is incorrect?(A) Thyroxine-bound receptors act on DNA and

regulate specific transcription of genes.(B) Cyclic adenosine monophosphate can act as a

second messenger.(C) The level of drug receptors at the cell surface

increases with chronic stimulation by receptor agonists.

(D) Binding of ligand to cell surface receptors can lead to synthesis of proteins.

(E) Antacids act by interacting with small ions normally found in the gastrointestinal tract.

6. A pharmacist is consulted about selecting a drug that is relatively safe and effective for treating the patient. He searches the literature and obtains the following data that may help guide his decision. The TD0.1 and ED99.9 for drug A are 20 mg and 0.4 mg, respectively; whereas the TD0.1 and ED99.9 for drug B are 15 mg and 0.2 mg, respectively. Which of the following statements is true?(A) Drug A has a higher TD0.1 and thus should be the

drug of choice.(B) Both drugs have the same margin of safety, so

more information is needed.(C) Drug B has a higher margin of safety and thus is

preferred to drug A.(D) Drug A is preferred because it has a greater

margin of safety than drug B.(E) The information obtained is irrelevant.

7. Which of the following statements concerning a drug receptor is true?(A) It is only found on the plasma membranes of

cells.(B) Its expression is induced only by exogenously

added drugs.(C) It can bind endogenous ligand to produce

physiological activity.(D) It is mostly composed of sugars (polysaccharides).(E) Receptor desensitization or downregulation have

no impact on the therapeutic effect of the drug.

8. Which of the following statements concerning morphine and hydromorphone (Dilaudid) is true?(A) Hydromorphone is a more effective analgesic

because it has a smaller ED50 than morphine.(B) Morphine and hydromorphone are equally potent

because they have the same Emax.(C) Morphine has a greater ED50 and is thus a less

effective analgesic than hydromorphone.(D) Hydromorphone is a more potent analgesic

because it has a greater Emax than morphine.(E) Hydromorphone has a smaller ED50 and thus is a

more potent analgesic than morphine.

1152 Chapter 58

9. A 72-year-old man with hypertension has been taking high-dose propranolol (Inderal) for 20 years. He left home for a week and forgot to bring his medication with him. One day, he was found collapsed on the floor and was brought to the emergency room. His blood pressure was 300/180, heart rate was 180 beats per minute, and retinal hemorrhage was observed. Which of the following best explains this situation?(A) The b-adrenergic receptors in the cardiac muscles

underwent spontaneous mutation and became hyperactive.

(B) Reduction in the chronic antagonism of the b-adrenergic receptor led to downregulation of the b-adrenergic receptor.

(C) The propranolol that he had previously ingested remained in his body and acted as a receptor agonist.

(D) Long-term administration of propranolol results in desensitization of cardiac muscles to endogenous b-adrenergic stimulation.

(E) Reduction in the chronic level of receptor blockade results in supersensitivity to stimulation with endogenous catecholamines.

10. A 42-year-old man with non-small cell lung carcinoma tells his pharmacist that his doctor had prescribed erlotinib (Tarceva) for treating his cancer. The patient asked what erlotinib is and how it works. His pharmacist explains to him that it is a drug that(A) prevents the binding of growth factors to their

receptors.(B) prevents growth factors from activating their

receptors.(C) boosts the functions of growth factor receptors.(D) neutralizes a receptor on cancer cells by an

antibody mechanism.

11. A 65-year-old woman experienced anginal pain with ST-segment elevation on electrocardiogram (ECG). She was treated with IV heparin, nitroglycerin, and atenolol (Tenormin) for acute myocardial infarction. Then 2 hrs later, when her nurse replaced her Foley bag, she noticed frank blood draining out of the Foley catheter. The physician checked the patient’s partial thrombin time, which was . 150 secs. The patient was then administered protamine, which acts by(A) promoting thrombosis.(B) reacting with and neutralizing the effect of

heparin.(C) directly inhibiting bleeding.(D) enhancing secretion of procoagulants.

12. Inverse agonist is a relatively new designation for drug action that a physician asks you about. Your explanation would include the fact that(A) these agents may have biological function by

altering the interaction between the receptor and G protein.

(B) there is no known drug with this type of effect.(C) these agents can desensitize receptors to agonist

stimulation.(D) the inverse form of these drugs can stimulate

physiological response.

13. A 55-year-old man with a history of heart disease was being treated with 20 mg of atorvastatin (Lipitor) but this was not adequate to bring his LDL cholesterol down to acceptable levels. So his physician increased the dose to 40 mg, which resulted in a 30% lowering in LDL. This would be an example of a(A) quantal dose–response relationship.(B) population dose–response relationship.(C) cumulative dose–response relationship.(D) graded dose–response relationship.

14. All of the following are examples of non–receptor-mediated drug effects except(A) magnesium sulfate for treatment of constipation.(B) calcium carbonate for relief of heartburn.(C) halothane for inducing anesthesia.(D) isopropyl alcohol used for its topical antibacterial

activity.(E) amphotericin B for fungal infections.

15. Which of the following salts will most likely yield an aqueous solution with a pH , 7?(A) Sodium salicylate(B) Potassium chloride(C) Magnesium sulfate(D) Potassium penicillin(E) Atropine sulfate

16. All of the following functional groups are weak bases except(A) aromatic amines.(B) sulfonamide.(C) tertiary amines.(D) imines.

17. The dissociation constant of a drug at its receptor is most closely related to(A) the maximal response produced by the drug.(B) the number of spare receptors available.(C) the affinity of the drug for the receptor.(D) the total number of receptors available to the drug.(E) allosterism.


18. All of the following statements about a structurally specific agonist are true except:(A) Activity is determined more by its chemical

structure than by its physical properties.(B) The entire molecule is involved in binding to a

specific endogenous receptor.(C) The drug cannot act unless it is first bound to a

receptor.(D) A minor structural change in a pharmacophore

can produce a loss in activity.(E) The higher the affinity between the drug and its

receptor, the greater the biological response.

19. The dextro (d) form of b-methacholine (structure shown) is approximately 500 times more active than the levo (l) enantiomer. The observed difference in pharmacological activity between the two isomers is most likely the result of differences in

(A) receptor selectivity.(B) dissolution.(C) distribution.(D) interatomic distance between pharmacophore

groups.(E) solubility.

20. The compound shown in the figure can be classified as a(n)

(A) acid.(B) base.(C) organic salt.(D) organic base.(E) inorganic salt.

21. Which of the following acids has the highest degree of ionization in an aqueous solution?(A) Aspirin; pKa 5 3.5(B) Indomethacin; pKa 5 4.5(C) Warfarin; pKa 5 5.1(D) Ibuprofen; pKa 5 5.2(E) Phenobarbital; pKa 5 7.4

22. The solid line on the graph in the following figure shows the change in mean blood pressure (from baseline of 90 mm Hg) with increasing bolus doses of angiotensin II in an experimental animal model. The dashed line is the response to the same doses of angiotensin II in the animal 2 hrs after an intravenous administration of 10 mg/kg of losartan, an antagonist of the angiotensin receptor. Based on the responses before and after the angiotensin antagonist, which of the following statements would most likely be true?

+ Losartan

100

50

0

Log angiotensin II dose

Mea

n bl

ood

pres

sure

(mm

Hg

from

bas

elin

e)(A) Angiotensin II is a partial agonist.(B) Losartan may interact irreversibly with the

angiotensin receptor.(C) Losartan is a partial agonist.(D) Angiotensin II may be an inverse agonist.(E) Angiotensin and losartan are probably working at

different sites in the animal.

23. The structure–activity relationship of a drug can be altered by all of the following parameters except(A) stereochemistry.(B) specific functional groups.(C) bioisosteric substitution.(D) cis–trans conformation.(E) the salt form of the drug.

24. Flurazepam has pKa of 8.2. What percentage of flurazepam will be ionized at a urine pH of 5.2?

FlurazepamDalmane

F

NCl

ON

N(C2H5)2

(A) 0.1%(B) 1%(C) 50%(D) 99%(E) 99.9%

1154 Chapter 58

25. Which of the following isomers can only be distinguished in a chiral environment or by measuring the direction of rotation of plane-polarized light in a polarimeter?(A) geometric isomers(B) enantiomers(C) diastereomers(D) bioisosteres

26. The organic functional groups responsible for a particular pharmacological activity are called a(n)(A) bioisostere.(B) eutomer.(C) epimer.(D) pharmacophore.(E) stereochemistry.

27. All of the following are basic functional groups except(A) guanidine.(B) primary amine.(C) amide.(D) amidine.(E) tertiary amine.

28. The partition coefficient (P) of a drug is best described as(A) the water solubility of a drug at a specific pH.(B) the presence of nonionizable functional groups

that make a drug lipid soluble.(C) the ratio of drug solubility in a lipophilic solvent

to solubility in an aqueous solvent.(D) the presence of ionizable functional groups that

make a drug water soluble.(E) the characterization of a drug as an acid or a base.

29. An inorganic salt of imide containing drug can be made by the addition of which of the following?(A) NaOH(B) H2SO4(C) HCl(D) HNO3(E) HBr

Directions for questions 30–34: The questions and incomplete statements in this section can be correctly answered or completed by one or more of the suggested answers. Choose the answer, A–E.

A if I only is correctB if III only is correctC if I and II are correctD if II and III are correctE if I, II, and III are correct

30. Which of the following statements may be true of drugs that are enzyme inhibitors?

I. They may be destroyed by the enzyme/receptor. II. They can bind to a site different from that of the

substrate. III. They can form covalent bonds with their receptors.

31. Examples of strong electrolytes (i.e., completely dissociated in an aqueous solution) include

I. acetic acid. II. pentobarbital sodium. III. diphenhydramine hydrochloride.

32. Precipitation may occur when mixing aqueous solutions of meperidine hydrochloride with which of the following solutions?

I. Sodium bicarbonate injection II. Atropine sulfate injection III. Sodium chloride injection

33. Drugs classified as synthetic include which of the following?

I. epinephrine II. morphine III. fondaparinux

34. The excretion of a weakly acidic drug is generally more rapid in alkaline urine than in acidic urine. This process occurs because

I. a weak acid in alkaline media will exist primarily in its ionized form, which cannot be reabsorbed easily.

II. a weak acid in alkaline media will exist in its lipophilic form, which cannot be reabsorbed easily.

III. all drugs are excreted more rapidly in an alkaline urine.

Questions 35–37: Refer to the drug meperidine (Demerol; structure shown).

35. Functional groups present in the molecule shown include I. an ester. II. a tertiary amine. III. a carboxylic acid.


36. Meperidine is classified as a I. weak acid. II. salt. III. weak base.

37. Assuming that meperidine is absorbed after oral administration and that a large percentage of the dose is excreted unchanged, the effect of alkalinization of the urine will increase its

I. duration of action. II. rate of excretion. III. ionization in the glomerular filtrate.

38. Which of the following statements regarding digoxin (Lanoxin) would be true?

I. It is a glycoside. II. It is a naturally occurring compound. III. It mimics the actions of an endogenous hormone.

Directions for questions 39–43: The relationship of each pair of structures shown in this section is most closely associated with one of the following terms. The terms may be used more than once or not at all. Choose the best answer, A–E.

(A) Geometric isomers(B) Enantiomers(C) Diastereomers(D) Bioisosteres(E) Conformational isomers

39.

40.

41.

N

N

H3C

H NN

H3C

H

1156 Chapter 58

42.

CH3CH2

O

O ONH

NH CH3CH2

O

O SNH

NH

43.

S

N

N(CH3)2

Cl

S

N Cl

(CH3)2N

1. The answer is A [see VII.D.1].The receptor would be a specific entity of the cell that drugs interact with to modify cell behavior. Although stomach acid is neutralized by antacids, it is not con-sidered a specific receptor.

2. The answer is E [see III.D.1].Lovastatin reversibly binds to the substrate-binding site of the enzyme HMG-CoA reductase, which catalyzes the rate-limiting step in the synthesis of cholesterol, thus lowering the cholesterol level. Therefore, lovas-tatin inhibits the enzyme by competitive antagonism.

3. The answer is E [see III.D.2].Aspirin can covalently modify the platelet cyclooxy-genase through acetylation of the enzyme other than the substrate-binding site, causing irreversible inhibi-tion of platelet aggregation. Therefore, aspirin inhibits platelet function by noncompetitive antagonism of cyclooxygenase.

4. The answer is E [see III.C.1].Naloxone is a competitive antagonist of opiate receptor. If one compares the log dose–response curve of both morphine and naloxone to that of morphine alone, the morphine–naloxone curve is shifted to the right. As a result, the ED50 for morphine is increased. This means that a larger than previous dose of morphine is required for achieving the same analgesic effect.

5. The answer is C [see III.E.2].The level of drug receptors at the cell surface usually decreases when the target cells are chronically stimu-lated by receptor agonists. Downregulation of recep-tors may be a protective mechanism that can prevent the target cells from being overstimulated.

6. The answer is C [see IV.C].The margin of safety of the two drugs can be helpful in guiding selection of a drug. Margin of safety is the ratio of TD0.1 to ED99.9. Thus, the margin of safety for drug A is 20 mg 4 0.4 mg, or 50, whereas the margin of safety for drug B is 15 mg 4 0.2 mg, or 75. Because drug B has a greater margin of safety than drug A, drug B is relative-ly safe at the dosage given to produce the desired effect.

7. The answer is C [see II.A; III.C; III.E.1–2].A drug receptor, such as muscarinic cholinergic recep-tor that can bind atropine, normally binds endogenous acetylcholine to produce the physiological responses controlled by the parasympathetic autonomic nervous system. Receptors may be found on plasma mem-branes, cytoplasm, or nuclei of cells and are primarily proteinaceous in nature, although they can have sugar or lipid modifications. Receptor downregulation may lead to the phenomenon of tachyphylaxis.

Answers and Explanations


8. The answer is E [see III.B.1].The efficacy of a drug is determined by its Emax, whereas its potency is measured by the ED50. Hydromorphone has a smaller ED50 and thus is a more potent analgesic than morphine. Hydromorphone and morphine are both agonists for opiate receptors, and they have the same analgesic efficacy (i.e., they have the same Emax) if sufficient amounts of both drugs are used.

9. The answer is E [see III.E.3].A chronic level of blocking the b-adrenergic receptors by propranolol results in upregulation of the receptor level. When the patient ceased taking the drug, the cardiac muscles became supersensitive to stimulation with endogenous catecholamines. This resulted in the hypertensive crisis that caused cerebral hemorrhage and loss of consciousness.

10. The answer is B [see III.C.4].Erlotinib is a small molecule that inhibits the tyrosine kinase domain of the epidermal growth factor (EGF) receptor on cancer cells.

11. The answer is B [see VII.D.1].Protamine is a chemical antagonist of heparin that acts via an acid–base interaction.

12. The answer is A [see III.C].Inverse agonists stabilize the form of the receptor that is not bound to G proteins and are not agonists in the classical sense. This uncoupling of receptor and G pro-tein may reduce basal cellular signaling even in the ab-sence of agonists. b- Receptor antagonists are thought to have this type of activity apart from preventing the actions of catecholamines.

13. The answer is D [see IV.B].Increasing doses of a drug usually produces greater responses and this is described as a graded response. This would be true in an individual or a population of patients.

14. The answer is C [see VII].All the choices have a nonreceptor mechanism for pro-ducing their effects except for halothane that activates inhibitory receptors on neurons.

15. The answer is E [see VI.B.6].The solution must contain an acidic substance to have a pH , 7. Atropine sulfate is a salt of a weak base and a strong acid; therefore, its aqueous solution is acidic. Sodium salicylate and potassium penicillin are both salts of strong bases and weak acids; therefore, their aqueous solutions are alkaline. Magnesium sul-fate and potassium chloride are salts of strong bases and strong acids; therefore, their aqueous solutions are neutral.

16. The answer is B [see VI.B.3–4; Table 58-2; Table 58-3].All these groups would accept a proton under physio-logical conditions except the sulfonamide, which would donate a proton instead.

17. The answer is C [see III.A].The dissociation constant of a drug is the concentra-tion at which half the available receptors are bound and the inverse of this value is the affinity of the drug– receptor interaction.

18. The answer is B [see V; VI].The binding of a drug to its receptor usually involves only specific functional groups. These groups make up what is known as the pharmacophore of the drug molecule. Although the entire drug molecule is pres-ent at the receptor site, only a portion of it, the phar-macophore, is required for a biological response. The affinity of drug–receptor interaction does not predict whether the drug behaves as an agonist (having biolog-ical activity) or an antagonist; in fact, antagonists often have higher affinities for the receptor than agonists.

19. The answer is A [see V.E.1].The term enantiomer and the d and l indicate that the b-methacholine has a chiral center and exhibits optical isomerism. Because the optical isomers have different orientations in space, one orientation will give a bet-ter fit than the other and will most likely have greater biological activity than the other. Dissolution, distri-bution, interatomic distances, and solubility are all related to the physical and chemical properties of the two compounds, which are identical because the com-pounds are enantiomers.

20. The answer is A [see VI.B.3; Table 58-2].The aryl sulfonamide donates a proton to behave as an acid due to the electron-withdrawing action of the aromatic ring.

21. The answer is A [see VI.B.2].The pKa (the negative log of the acid ionization con-stant) indicates the relative strength of an acidic drug. The lower the pKa of an acidic drug, the stronger it is as an acid. A strong acid is defined as one that is complete-ly ionized or dissociated in an aqueous solution; there-fore, the stronger the acid, the greater the ionization.

22. The answer is B [see III.C.2].The decrease in the maximal angiotensin II effect (Emax) after treatment with losartan would indicate that the number of receptors available to produce drug effect has been reduced. This occurs when antagonist interacts in an irreversible manner with the receptor and leaves only a limited number of receptors through which the agonist can only produce a less than maxi-mal response.

1158 Chapter 58

23. The answer is E [see V.A–E].All of the choices except the salt form of the drug would influence the interaction of the drug with its receptor.

24. The answer is E [see VI.B.5].Flurazepam (take note of the suffix, which helps clas-sify the compound) is a benzodiazepine and thus a basic compound. Because the pH is less than the pKa, flurazepam is in an acidic environment and therefore exists primarily in the ionized form. The percentage ionized can be easily calculated by using the rule of nines. The |pH 2 pKa| is 3, so the ratio is 99.9%:0.01% in favor of the ionized form.

25. The answer is B [see V.E.1.a & d].Enantiomers are nonsuperimposable mirror images of each other that have identical physical and chemical properties except for the rotation of plane-polarized light. Enantiomers are distinguishable in a chiral en-vironment. Geometric isomers, diastereomers, and bioisosteres each have unique physical and chemical properties.

26. The answer is D [see V.B; V.D; V.E.1.c; V.E.2.b].The pharmacophore describes the critical organic functional groups and their spatial relationship within a drug molecule required for a specific pharmacologi-cal activity. A bioisostere is a compound containing an atom or group of atoms that is spatially and elec-tronically similar to another molecule that produces a similar biological activity. A eutomer is one of a pair of enantiomers that has the desired pharmacological activity. The other isomer is the distomer that may not have pharmacological activity or may cause ad-verse effects. Epimers are a pair of compounds that have exactly the same stereochemistry in all positions except one.

27. The answer is C [see VI.B.4; Table 58-1; Table 58-3].Primary and tertiary amines are basic because they have a free pair of electrons that can accept a pro-ton. The quaternary amines are neutral because there are no free electrons available to accept a proton. Guanidines and amidines also have free electrons to accept a proton and therefore they are basic function-al groups. Amides are neutral compounds although they appear to have a free pair of electrons like the amines, but the difference is that the electrons on the amide nitrogen are in resonance with the double bond on the carbonyl, making them unavailable to accept a proton.

28. The answer is C [see VI.A.1].The partition coefficient is defined as the ratio of the solubility of an agent in an organic lipophilic solvent (i.e., n-octanol) to its solubility in an aqueous buffer. The functional groups present, either ionizable or non-ionizable, influence the partition coefficient.

29. The answer is A [see Table 58-2; VI.B.3.a, 4.a, & 6.a].The imide is a weak acid, so adding a strong base like sodium hydroxide (NaOH) or potassium hydroxide (KOH) will produce an inorganic salt. All the other choices (i.e., sulfuric acid, hydrochloric acid, nitric acid, and hydrobromic acid) are strong acids and would not produce a salt upon addition to the weak acid imide.

30. The answer is E (I, II, and III) [see III.D].Suicide inhibitors are drugs that are metabolized or destroyed in the process of inhibiting enzymatic activity, whereas allosteric inhibitors target a site distinct from that for the substrate. Some drugs interact irreversibly with their enzyme target due to covalent bonding.

31. The answer is D (II, III) [see VI.B.6].Almost all salts (with very few exceptions) are strong electrolytes, and the terminology pentobarbital sodium and diphenhydramine hydrochloride indicates that each compound is salt. Acetic acid is a weak acid; therefore, it is a weak electrolyte.

32. The answer is A (I) [see VI.B].When meperidine hydrochloride solution is mixed with the alkaline solution of sodium bicarbonate, a neutralization reaction occurs with the possible pre-cipitation of the water-insoluble free base meperidine. A neutralization reaction occurs when acidic solutions are mixed with basic solutions, or conversely. No reac-tion, in terms of acid–base, occurs when solutions are mixed with other acidic or neutral solutions or when basic solutions are mixed with other basic or neutral solutions. There should be no reaction, then, when the meperidine hydrochloride solution, which is acidic, is mixed with the acidic solution of atropine sulfate or the neutral solution of sodium chloride.

33. The answer is B (III) [see VIII.B.3].Both epinephrine and morphine are naturally occur-ring, whereas fondaparinux is a synthetic derivative of heparin.

34. The answer is A (I) [see VI.B].A weakly acidic drug will be more ionized in an al-kaline urine; therefore, it will be more polar and thus more soluble in the aqueous urine. It would also be less liposoluble, less likely to undergo tubular reabsorption, and thus more likely to be excreted.

35. The answer is C (I, II) [see VI.B; Table 58-1].The molecule contains a basic nitrogen, which is bond-ed to three carbon atoms (i.e., a tertiary amine), and an ethyl carboxylate, which is an ester group. An ester is the product of the reaction of an alcohol with a carbox-ylic acid that forms an alkyl carboxylate. There is no free carboxylic acid present. However, if this molecule is subjected to hydrolysis, it forms a carboxylic acid and ethyl alcohol.


36. The answer is B (III) [see VI.B; Table 58-3].Because meperidine contains a tertiary amine, it is clas-sified as a base; because it is an organic base, it is consid-ered weak. The nitrogen is not protonated. It is not ionic and therefore is not a salt.

37. The answer is A (I) [see VI.B].Alkalinization of the urine decreases the ionization of meperidine, making it more liposoluble and thus more likely to undergo reabsorption in the kidney tubule. This results in a decreased rate of excretion and an in-creased duration of action. The six-member, nonaro-matic ring is a piperidine ring that is substituted at the 4-position (nitrogen is position 1) with a phenyl ring. The compound does not contain a piperazine ring or a propyl group.

38. The answer is C (I, II) [see VIII.A].The cardiac glycoside digoxin occurs naturally in fox-glove and strophanthus plants but it does not substitute or mimic the actions of endogenous hormones.

39. The answer is C [see V.E.2].These molecules are isomers that have two asymmet-ric carbon atoms. They are not superimposable and are not mirror images; therefore, they are known as diastereomers.

40. The answer is B [see V.E.1].These molecules are isomers that have one asymmet-ric carbon atom. They are nonsuperimposable mirror images; therefore, they are enantiomers.

41. The answer is A [see V.E.2.c].These molecules have different spatial arrangements; however, these molecules do not have an asymmetric center. The presence of the double bond, which re-stricts the rotation of the groups on each carbon atom involved in the double bond, characterizes this type of isomerism as geometric.

42. The answer is D [see V.D].These molecules are neither isomers nor the same compound because one contains three oxygens, where-as the other contains two oxygens and a sulfur. Because oxygen and sulfur are in the same periodic family, they are isosteric and are known as bioisosteres.

43. The answer is E [see V.E.3].These structures are actually two views of the same compound. Rotation around the side chain single bonds connecting the ring nitrogen to the tertiary nitrogen produces these two different conformations. Thus, these are conformational isomers.

s. thomas abraham, michael l. adams

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