Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition

Name: Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition
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Author: Laurence Brunton; Bruce A. Chabner; Bjorn Knollman
ISBN: 9780071769396

Höfundar: Laurence Brunton; Bruce A. Chabner; Bjorn Knollman (Útgáfa: 12)

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The landmark text in medical pharmacology is now in full color Includes DVD with image bank A Doody's Core Title ESSENTIAL PURCHASE for 2011! 4 STAR DOODY'S REVIEW! "This 12th edition of the most authoritative book in pharmacology is the best both in content and physical appearance. . . . This edition of Goodman & Gilman's continues to be the most authoritative and widely used resource bridging the discipline of pharmacology with therapeutics.

Moreover, readers will find this edition to be substantially improved from past editions in both content and physical appearance. "--Doody's Review Service The most universally respected and read medical text in all of pharmacology, Goodman & Gilman’s The Pharmacological Basis of Therapeutics represents the pinnacle of authority and accuracy in describing the actions and uses of therapeutic agents in relation to physiology and pathophysiology.

Goodman & Gilman’s careful balance of basic science and clinical application has guided thousands of practitioners and students to a clear understanding of the drugs essential to preventing, diagnosing, and treating disease. Enriched by a new full-color presentation and updated to reflect all critical new developments in drug action and drug-disease interaction, the twelfth edition includes more than 440 color illustrations depicting key principles and actions of specific pathways and therapeutic agents.

The companion DVD includes all the images and tables in the text along with narrated animations. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e is divided into nine sections, covering: General Principles Neuropharmacology Modulation of Cardiovascular Function Inflammation, Immunomodulation, and Hematopoiesis Endocrine Pharmacology Gastrointestinal Pharmacology Chemotherapy of Infectious Disease Chemotherapy of Neoplastic Diseases Special Systems Pharmacology More than a textbook, Goodman & Gilman's is a working template for the effective and rational prescribing of drugs in daily practice.

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Útgefandi: McGraw-Hill Professional

ISBN: 9780071769396

Print ISBN: 9780071624428

Format: ePub

Útgáfa: 12

Höfundar: Laurence Brunton; Bruce A. Chabner; Bjorn Knollman

Tungumál: English

Útgefið: 2011-01-14

Prent takmörkun á líftíma: 10

Prent takmörkun: 2

Afritunar takmörkun: 2

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Front Matter
Contents
Contributors
Preface
Preface to the First Edition
Acknowledgments
Section I General Principles
chapter 1 Drug Invention and the Pharmaceutical Industry
FROM EARLY EXPERIENCES WITH PLANTS TO MODERN CHEMISTRY
SOURCES OF DRUGS
Small Molecules Are the Tradition
From Hits to Leads
Large Molecules Are Increasingly Important
TARGETS OF DRUG ACTION
Is the Target "Drugable"?
Has the Target Been Validated?
Is This Drug Invention Effort Economically Viable?
ADDITIONAL PRECLINICAL RESEARCH
CLINICAL TRIALS AND THE ROLE OF THE FDA
The Conduct of Clinical Trials
Table 1-1 Typical Characteristics of the Various Phases of the Clinical Trials Required for Marketing of New Drugs.
Figure 1-1. The phases, time lines, and attrition that characterize the invention of new drugs. See also Table 1-1.
Determining "Safe" and "Effective"
PUBLIC POLICY CONSIDERATIONS AND CRITICISMS OF THE PHARMACEUTICAL INDUSTRY
Mistrust of Scientists and Industry
Pricing and Profitability
Who Pays?
Intellectual Property and Patents
Drug Promotion
Exploitation or "Medical Imperialism"
Product Liability
"Me Too" Versus True Innovation: The Pace of New Drug Development
Figure 1-2. The cost of drug invention is rising dramatically while productivity is declining. The past several decades have seen enormous increases in spending for research and development by the pharmaceutical industry. While this was associated with increasing numbers of new molecular entities (NMEs) approved for clinical use during the latter years of the 20th century, this trend has been reversed over the past decade, leading to unsustainable costs per new molecular entity approved by the FDA. The peak in the mid-1990s was caused by the advent of PDUFA (see text), which facilitated elimination of a backlog.
BIBLIOGRAPHY
chapter 2 Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination
PHYSICOCHEMICAL FACTORS IN TRANSFER OF DRUGS ACROSS MEMBRANES
Figure 2-1 The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. Possible distribution and binding of metabolites in relation to their potential actions at receptors are not depicted.
Figure 2-2. The variety of ways drugs move across cellular barriers in their passage throughout the body.
(Equation 2-1)
Figure 2-3 Influence of pH on the distribution of a weak acid between plasma and gastric juice separated by a lipid barrier. A. The dissociation of a weak acid, pKa = 4.4. B. Dissociation of the weak acid in plasma (pH 7.4) and gastric acid (pH 1.4). The uncharged from, HA, equibrates across the membrane. Blue numbers in brackets show relative concentrations of HA and A−.
DRUG ABSORPTION, BIOAVAILABILITY, AND ROUTES OF ADMINISTRATION
Table 2-1 Some Characteristics of Common Routes of Drug Administrationa
Topical Application
Novel Methods of Drug Delivery
Bioequivalence
DISTRIBUTION OF DRUGS
EXCRETION OF DRUGS
METABOLISM OF DRUGS
CLINICAL PHARMACOKINETICS
Clearance
(Equation 2-2)
(Equation 2-3)
(Equation 2-4)
(Equation 2-5)
(Equation 2-6)
(Equation 2-7)
(Equation 2-8)
(Equation 2-9)
DISTRIBUTION
(Equation 2-10)
(Equation 2-11)
Figure 2-4 Plasma concentration-time curves following intravenous administration of a drug (500 mg) to a 70-kg patient. A. Drug concentrations are measured in plasma at 2-hour intervals following drug administration. The semi-logarithmic plot of plasma concentration (Cp) versus time appears to indicate that the drug is eliminated from a single compartment by a first-order process (Equation 2-11) with a t1/2 of 4 hours (k = 0.693/t1/2 = 0.173 hr-1). The volume of distribution (V) may be determined from the value of Cp obtained by extrapolation to t = 0 (Cpo = 16 µg/mL). Volume of distribution (Equation 2-10) for the one-compartment model is 31.3 L, or 0.45 L/kg (V = dose/Cpo). The clearance for this drug is 90 mL/min; for a one-compartment model, CL = kV. B. Sampling before 2 hours indicates that in fact the drug follows multi-exponential kinetics. The terminal disposition t1/2 is 4 hours, clearance is 84 mL/min (Equation 2-6), Varea is 29 L (Equation 2-11), and Vss is 26.8 L. The initial or "central" distribution volume for the drug (V1 = dose/Cpo) is 16.1 L. The example chosen indicates that multicompartment kinetics may be overlooked when sampling at early times is neglected. In this particular case, there is only a 10% error in the estimate of clearance when the multicompartment characteristics are ignored. For many drugs, multicompartment kinetics may be observed for significant periods of time, and failure to consider the distribution phase can lead to significant errors in estimates of clearance and in predictions of the appropriate dosage. Also, the difference between the "central" distribution volume and other terms reflecting wider distribution is important in deciding a loading dose strategy.
(Equation 2-12)
(Equation 2-13)
Figure 2-5 Fundamental pharmacokinetic relationships for repeated administration of drugs. The blue line is the pattern of drug accumulation during repeated administration of a drug at intervals equal to its elimination half-time when drug absorption is 10 times as rapid as elimination. As the rate of absorption increases, the concentration maxima approach 2 and the minima approach 1 during the steady state. The black line depicts the pattern during administration of equivalent dosage by continuous intravenous infusion. Curves are based on the one-compartment model. Average concentration () when the steady state is attained during intermittent drug administration is where F is fractional bioavailability of the dose and T is dosage interval (time). By substitution of infusion rate for F · dose/T, the formula is equivalent to Equation 2-2 and provides the concentration maintained at steady state during continuous intravenous infusion.
(Equation 2-14)
Extent and Rate of Bioavailability
(Equation 2-15)
(Equation 2-16)
Nonlinear Pharmacokinetics
(Equation 2-17)
Design and Optimization of Dosage Regimens
Figure 2-6 Temporal characteristics of drug effect and relationship to the therapeutic window (e.g., single dose, oral administration). A lag period is present before the plasma drug concentration (Cp) exceeds the minimum effective concentration (MEC) for the desired effect. Following onset of the response, the intensity of the effect increases as the drug continues to be absorbed and distributed. This reaches a peak, after which drug elimination results in a decline in Cp and in the effect's intensity. Effect disappears when the drug concentration falls below the MEC. Accordingly, the duration of a drug's action is determined by the time period over which concentrations exceed the MEC. An MEC exists for each adverse response, and if drug concentration exceeds this, toxicity will result. The therapeutic goal is to obtain and maintain concentrations within the therapeutic window for the desired response with a minimum of toxicity. Drug response below the MEC for the desired effect will be subtherapeutic; above the MEC for an adverse effect, the probability of toxicity will increase. Increasing or decreasing drug dosage shifts the response curve up or down the intensity scale and is used to modulate the drug's effect. Increasing the dose also prolongs a drug's duration of action but at the risk of increasing the likelihood of adverse effects. Unless the drug is nontoxic (e.g., penicillins), increasing the dose is not a useful strategy for extending the duration of action. Instead, another dose of drug should be given, timed to maintain concentrations within the therapeutic window. The area under the blood concentration-time curve (area under the curve, or AUC, shaded in gray) can be used to calculate the clearance (Equation 2-6) for first-order elimination. The AUC is also used as a measure of bioavailability (defined as 100% for an intravenously administered drug). Bioavailability will be <100% for orally administered drugs, due mainly to incomplete absorption and first-pass metabolism and elimination.
Maintenance Dose
(Equation 2-18)
(Equation 2-19)
(Equation 2-20)
(Equation 2-21)
Loading Dose
(Equation 2-22)
Individualizing Dosage
Therapeutic Drug Monitoring
(Equation 2-23)
(Equation 2-24)
BIBLIOGRAPHY
chapter 3 Pharmacodynamics: Molecular Mechanisms of Drug Action
PHARMACODYNAMIC CONCEPTS
Physiological Receptors
Drug Specificity
Figure 3-1. Regulation of the activity of a receptor with conformation-selective drugs. The ordinate is the activity of the receptor produced by Ra, the active receptor conformation (e.g., stimulation of adenylyl cyclase by a β adrenergic receptor). If a drug L selectively binds to Ra, it will produce a maximal response. If L has equal affinity for Ri and Ra, it will not perturb the equilibrium between them and will have no effect on net activity; L would appear as an inactive compound. If the drug selectively binds to Ri, then the net amount of Ra will be diminished. If L can bind to receptor in an active conformation Ra but also bind to inactive receptor Ri with lower affinity, the drug will produce a partial response; L will be a partial agonist. If there is sufficient Ra to produce an elevated basal response in the absence of ligand (agonist-independent constitutive activity), then activity will be inhibited; L will then be an inverse agonist. Inverse agonists selectively bind to the inactive form of the receptor and shift the conformational equilibrium toward the inactive state. In systems that are not constitutively active, inverse agonists will behave like competitive antagonists, which helps explain why the properties of inverse agonists and the number of such agents previously described as competitive antagonists were only recently appreciated. Receptors that have constitutive activity and are sensitive to inverse agonists include benzodiazepine, histamine, opioid, cannabinoid, dopamine, bradykinin, and adenosine receptors.
Structure-Activity Relationships and Drug Design
QUANTITATIVE ASPECTS OF DRUG INTERACTIONS WITH RECEPTORS
Figure 3-2. Graded responses (y axis as a percentage of maximal response) expressed as a function of the concentration of drug A present at the receptor. The hyperbolic shape of the curve in panel A becomes sigmoid when plotted semi-logarithmically, as in panel B. The concentration of drug that produces 50% of the maximal response quantifies drug activity and is referred to as the EC50 (effective concentration for 50% response). The range of concentrations needed to fully depict the dose-response relationship (~3 log10 [10] units) is too wide to be useful in the linear format of Figure 3-2A; thus, most dose-response curves use log [Drug] on the x axis, as in Figure 3-2B. Dose-response curves presented in this way are sigmoidal in shape and have three properties: threshold, slope, and maximal asymptote. These three parameters quantitate the activity of the drug.
(Equation 3-1)
(Equation 3-2)
(Equation 3-3)
(Equation 3-4)
Figure 3-3. Two ways of quantifying agonism. A. The relative potency of two agonists (Drug X, red line; Drug Y, purple line) obtained in the same tissue is a function of their relative affinities and intrinsic efficacies. The EC50 of Drug X occurs at a concentration that is one-tenth the EC50 of Drug Y. Thus, Drug X is more potent than Drug Y. B. In systems where the two drugs do not both produce the maximal response characteristic of the tissue, the observed maximal response is a nonlinear function of their relative intrinsic efficacies. Drug X is more efficacious than Drug Y; their asymptotic fractional responses are 100% (Drug X) and 50% (Drug Y).
Figure 3-4. Mechanisms of receptor antagonism. A. Competitive antagonism occurs when the agonist A and antagonist I compete for the same binding site on the receptor. Response curves for the agonist are shifted to the right in a concentration-related manner by the antagonist such that the EC50 for the agonist increases (e.g., L versus L′, L″, and L‴) with the concentration of the antagonist. B. If the antagonist binds to the same site as the agonist but does so irreversibly or pseudo-irreversibly (slow dissociation but no covalent bond), it causes a shift of the dose-response curve to the right, with further depression of the maximal response. Allosteric effects occur when an allosteric ligand I or P binds to a different site on the receptor to either inhibit (I) the response (see panel C) or potentiate (P) the response (see panel D). This effect is saturable; inhibition or potentiation reaches a limiting value when the allosteric site is fully occupied.
(Equation 3-5)
(Equation 3-6)
(Equation 3-7)
(Equation 3-8)
PHARMACODYNAMIC VARIABILITY: INDIVIDUAL AND POPULATION PHARMACODYNAMICS
Figure 3-5. Frequency distribution curves and quantal concentration-effect and dose-effect curves. A. Frequency distribution curves. An experiment was performed on 100 subjects, and the effective plasma concentration that produced a quantal response was determined for each individual. The number of subjects who required each dose is plotted, giving a log-normal frequency distribution (purple bars). The red bars demonstrate that the normal frequency distribution, when summated, yields the cumulative frequency distribution—a sigmoidal curve that is a quantal concentration-effect curve. B. Quantal dose-effect curves. Animals were injected with varying doses of a drug and the responses were determined and plotted. The calculation of the therapeutic index, the ratio of the LD50 to the ED50, is an indication of how selective a drug is in producing its desired effects relative to its toxicity. See text for additional explanation.
Figure 3-6. The relation of the therapeutic window of drug concentrations to the therapeutic and adverse effects in the population. The ordinate is linear; the abcissa is logarithmic.
Figure 3-7. Factors that influence the relationship between prescribed dosage and drug effects. (Modified with permission from Koch-Weser J. Serum drug concentrations as therapeutic guides. N Engl J Med, 1972, 287:227–231. Copyright © Massachusetts Medical Society. All rights reserved.)
MECHANISMS OF DRUG ACTION
Receptors That Affect Concentrations of Endogenous Ligands
Receptors That Regulate the Ionic Milieu
Cellular Pathways Activated by Physiological Receptors
Structural and Functional Families of Physiological Receptors
G Protein-Coupled Receptors (GCPRs)
Table 3-1 Physiological Receptors
Figure 3-8. Diagram showing the stimulation of a G-protein coupled receptor by ligand, the activation of the G protein, and stimulation of selected effectors. Schematic diagram of the mechanisms involved in the control of cell function by G-protein coupled receptors, G proteins, and effectors. In the absence of ligand, the receptor and G protein heterotrimer form a complex in the membrane with the Gα subunit bound to GDP. Following binding of ligand, the receptor and G protein α subunit undergo a conformational change leading to release of GDP, binding of GTP, and dissociation of the complex. The activated GTP-bound Gα subunit and the freed βγ dimer bind to and regulate effectors. The system is returned to the basal state by hydrolysis of the GTP on the α subunit; a reaction that is markedly enhanced by the RGS proteins. Prolonged stimulation of the receptor can lead to down-regulation of the receptor. This event is initiated by G protein receptor kinases (GRKs) that phosphorylate the C terminal tail of the receptor, leading to recruitment of proteins termed arrestins; arrestins bind to the receptor on the internal surface, displacing G proteins and inhibiting signaling. Detailed descriptions of these signaling pathways are given throughout the text in relation to the therapeutic actions of drugs affecting these pathways.
Second Messengers
Other Second Messengers
Ion Channels
Figure 3-9. Schematic diagram of two types of ion channels regulated by receptors and drugs. A. Diagram of a voltage-activated Na+ channel with the pore in the open and closed state. The P loops are shown in blue, angled into the pore to form the selectivity filter. The S4 helices forming the voltage sensor are shown in orange, with the positively charged amino acids displayed as red dots. B. Ligand-gated nicotinic acetylcholine receptor expressed in the skeletal muscle neuromuscular junction. The pore is made up of five subunits, each with a large extracellular domain and four transmembrane helices (one of these subunits is shown at the left of panel B). The helix that lines the pore is shown in blue. The receptor is composed of 2 α subunits, and β, γ, and δ subunits. See text for discussion of other ligand-gated ion channels. Detailed descriptions of specific channels are given throughout the text in relation to the therapeutic actions of drugs affecting these channels (see especially Chapters 11, 14 and 20). (Adapted with permission from Purves, D, Augustine, GJ, Fitzpatrick, D, Hall, WC, LaMantia, AS, McNamara, JO, and White, LE (eds). Neuroscience, 4ed. Sinauer Associates, Inc., 2008.)
Transmembrane Receptors Linked to Intracellular Enzymes
Figure 3-10. Diagram showing the mechanism of activation of a receptor tyrosine kinase and a cytokine receptor. A. Activation of the EGF receptor. The extracellular structure of the unliganded receptor (a) contains four domains (I-IV), which rearrange significantly upon binding two EGF molecules. (b). The conformational changes lead to activation of the cytoplasmic tyrosine kinase domains and tyrosine phosphorylation of intracellular regions to form SH2 binding sites. (c). The adapter molecule Grb2 binds to the phosphoryated tyrosine residues and activates the Ras-MAP kinsase cascade. B. Activation of a cytokine receptor. Binding of the cytokine causes dimerization of the receptor and recruits the Janus Kinases (JAKs) to the cytoplasmic tails of the receptor. JAKs trans-phosphorylate and lead to the phosphorylation of the signal transducers and activators of transcription (STATs). The phosphorylated STATS translocate to the nucleus and regulate transcription. There are proteins termed suppressors of cytokine signaling (SOCS) that inhibit the JAKSTAT pathway (Alexander and Hilton, 2004).
Receptors That Stimulate Synthesis of Cyclic GMP
Figure 3-11. Cyclic GMP signaling pathways. Formation of cyclic GMP is regulated by cell surface receptors with intrinsic guanlyate cyclase activity and by soluble forms of guanylate cyclase (GC). The cell surface receptors respond to natriuretic peptides such as atrial natriuretic peptide (ANP) with an increase in cyclic GMP. Soluble guanylate cyclase responds to nitric oxide (NO) generated from L-arginine by nitric oxide synthase (NOS). Cellular effects of cyclic GMP are carried out by PKG and cyclic GMP-regulated phosphodiesterases (PDEs). In this diagram, NO is produced by a Ca2+/calmodulin-dependent NOS in an adjacent endothelial cell. Detailed descriptions of these signaling pathways are given throughout the text in relation to the therapeutic actions of drugs affecting these pathways.
NUCLEAR HORMONE RECEPTORS AND TRANSCRIPTION FACTORS
Figure 3-12. Diagram of nuclear hormone receptor activation. A nuclear hormone receptor (OR) is shown in complex with the retinoic acid receptor (RXR). When an agonist (yellow triangle) and co-activator bind, a conformational change occurs in helix 12 (black bar) and gene transcription is stimulated. If co-repressors are bound, activation does not occur. See text for details; see also Figure 6-13.
APOPTOSIS
Figure 3-13. Two pathways leading to apoptosis. Apoptosis can be initiated by external ligands such as TNF, FAS, or TRAIL at specific transmembrane receptors (left half of figure). Activation leads to trimerization of the receptor, and binding of adaptor molecules such as TRADD, to the intracellular death domain. The adaptors recruit caspase 8, activate it leading to cleavage and activation of the effector caspase, caspase 3, which activates the caspase pathway, leading to apoptosis. Apoptosis can also be initiated by an intrinsic pathway regulated by Bcl-2 family members suc as BAX and Bcl-2. BAX is activated by DNA damage or malformed proteins via p53 (right half of figure). Activation of this pathway leads to release of cytochrome c form the mitochondria, formation of a complex with Apaf-1 and caspase 9. Caspase 9 is activated in the complex and initiates apoptosis thru activation of caspase 3. Either the extrinsic or the intrinsic pathway can overwhelm the inhibitors of apoptosis proteins (IAPs) that otherwise keep apoptosis in check. See text for details.
RECEPTOR DESENSITIZATION AND REGULATION OF RECEPTORS
PHARMACODYNAMIC INTERACTIONS IN A MULTICELLULAR CONTEXT
Figure 3-14. Interaction of multiple signaling systems regulating vascular smooth muscle cells. The membrane receptors and channels are sensitive to pharmacological antagonists. See text for explanation of signaling and contractile pathways and abbreviations.
BIBLIOGRAPHY
chapter 4 Drug Toxicity and Poisoning
DOSE-RESPONSE
Figure 4-1. Dose-response relationships. A. The toxic response to a chemical is evaluated at several doses in the toxic or lethal range. The midpoint of the curve representing percent of population responding (response here is death) versus dose (log scale) represents the LD50, or the concentration of drug that is lethal in 50% of the population. B. A linear transformation of the data in panel A, obtained by plotting the log of the dose administered versus the percent of the population killed, in probit units.
Figure 4-2. Comparison of effective dose (ED), and lethal dose (LD). See text for explanation of probit units. Note that abscissa is a logarithmic scale.
Figure 4-3. U-Shaped dose-response curve for essential metals and vitamins. Vitamins and essential metals are essential for life and their lack can cause adverse responses (plotted on the vertical axis), as can their excess, giving rise to a U-shaped concentration-dependence curve.
PHARMACOKINETICS VERSUS TOXICOKINETICS
Table 4-1 Drugs That Commonly Manifest Initial Symptoms More Than 4–6 Hours after Oral Overdosea
Figure 4-4. Spectrum of the effects of pharmaceuticals.
Types of Therapeutic Drug Toxicity
Figure 4-5. Pathways of acetaminophen metabolism and toxicity. The toxic intermediate NAPQI is N-acetyl-p-benzoquinoneimine.
Figure 4-6. Mechanisms and classification of drug interactions.
DESCRIPTIVE TOXICITY TESTING IN ANIMALS
TOXICOLOGY, SAFETY TESTING, AND CLINICAL TRIALS
EPIDEMIOLOGY OF ADVERSE DRUG RESPONSES AND PHARMACEUTICAL POISONING
Table 4-2 Potential Scenarios for the Occurrence of Poisoning
Table 4-3 Top Five Agents Involved in Drug-Related Deaths
Table 4-4 Substances Most Frequently Involved in Human Poisoning Exposures
Table 4-5 Poisons Associated with the Largest Number of Human Fatalities
PREVENTION OF POISONING
Figure 4-7. The "Swiss cheese" model of medication error. Several checkpoints typically exist to identify and prevent an adverse drug event, and that adverse event can only occur if holes in several systems align. A. One systematic error does not lead to an adverse event, because it is prevented by another check in the system. B. Several systematic errors align to allow an adverse event to occur. (Adapted from Reason, 2000.)
Table 4-6 Best Practice Recommendations to Reduce Medication Administration Errorsa
Table 4-7 Passive Poisoning Prevention Strategies and Examples
PRINCIPLES OF TREATMENT OF POISONING
Table 4-8 ABCDE: Initial Treatment Approach for Acute Poisoning
Table 4-9 Common Toxidromes
Table 4-10 Differential Poisoning Diagnosis (Partial Listing) for Electrocardiographic Manifestations of Toxicity
IMPORTANT RESOURCES FOR INFORMATION RELATED TO DRUG TOXICITY AND POISONING
Table 4-11 Some Common Antidotes and Their Indications
BIBLIOGRAPHY
chapter 5 Membrane Transporters and Drug Response
MEMBRANE TRANSPORTERS IN THERAPEUTIC DRUG RESPONSES
Figure 5-1. Roles of membrane transporters in pharmacokinetic pathways. Membrane transporters (T) play roles in pharmacokinetic pathways (drug absorption, distribution, metabolism, and excretion), thereby setting systemic drug levels. Drug levels often drive therapeutic and adverse drug effects.
Figure 5-2. Hepatic drug transporters. Membrane transporters, shown as red ovals with arrows, work in concert with phase 1 and phase 2 drug-metabolizing enzymes in the hepatocyte to mediate the uptake and efflux of drugs and their metabolites.
MEMBRANE TRANSPORTERS AND ADVERSE DRUG RESPONSES
Figure 5-3. Major mechanisms by which transporters mediate adverse drug responses. Three cases are given. The left panel of each case provides a cartoon representation of the mechanism; the right panel shows the resulting effect on drug levels. (Top panel) Increase in the plasma concentrations of drug due to a decrease in the uptake and/or secretion in clearance organs such as the liver and kidney. (Middle panel) Increase in the concentration of drug in toxicological target organs due either to the enhanced uptake or to reduced efflux of the drug. (Bottom panel) Increase in the plasma concentration of an endogenous compound (e.g., a bile acid) due to a drug's inhibiting the influx of the endogenous compound in its eliminating or target organ. The diagram also may represent an increase in the concentration of the endogenous compound in the target organ owing to drug-inhibited efflux of the endogenous compound.
BASIC MECHANISMS OF MEMBRANE TRANSPORT
(Equation 5-1)
(Equation5-2)
(Equation 5-3)
Figure 5-4. Classification of membrane transport mechanisms. Red circles depict the substrate. Size of the circles is proportional to the concentration of the substrate. Arrows show the direction of flux. Black squares represent the ion that supplies the driving force for transport (size is proportional to the concentration of the ion). Blue ovals depict transport proteins.
(Equation 5-4)
(Equation 5-5)
(Equation 5-6)
(Equation 5-7)
KINETICS OF TRANSPORT
(Equation 5-8)
(Equation 5-9)
(Equation 5-10)
(Equation 5-11)
(Equation 5-12)
VECTORIAL TRANSPORT
Figure 5-5. Transepithelial or transendothelial flux. Transepithelial or transendothelial flux of drugs requires distinct transporters at the two surfaces of the epithelial or endothelial barriers. These are depicted diagrammatically for transport across the small intestine (absorption), the kidney and liver (elimination), and the brain capillaries that comprise the blood-brain barrier.
MOLECULAR STRUCTURES OF TRANSPORTERS
Table 5-1 Regulation of Transporter Expression by Nuclear Receptors
TRANSPORTER SUPERFAMILIES IN THE HUMAN GENOME
Figure 5-6. Predicted secondary structure of MRP2 based on hydropathy analysis. The dark blue circles depict glycosylation sites; Walker A motif is colored light blue; black boxes represent the Walker B motif. Light gray is the middle region between the two motifs. The Walker A motifs interact with α and β phosphates of di- and tri-nucleotides; the Walker B motifs help to coordinate Mg2.
Figure 5-7. Structure of four crystallized ABC transporters from microorganisms. The structures show the intracellular nucleotide binding domains (NBDs) along with the transmembrane alpha helices. Structure was reconstructed by Libusha Kelly using the coordinates deposited in the Protein Data Bank (PDB; http://www.rcsb.org/pdb/).
Figure 5-8. Structure of the protonated form of a mutant of LacY. Two units of six-membrane-spanning α-helices (shown as ribbons) are present. Substrate (depicted as green and black balls) is bound to the interface of the two units and in the middle of the membrane. Structure has been redrawn from coordinates in Protein Data Bank (http://www.rcsb.org/pdb/).
Figure 5-9. Alternating access models of the transport function of two transporters. The gated pore represents the model for SGLT in which the rotation of two broken helices facilitates alternating access of substrates to the intracellular and extracellular sides of the plasma membrane. The rocker switch represents the model by which MFS proteins, such as LacY, work. This example models a facilitated glucose transporter, GLUT2.
Table 5-2 Families in the Human Solute Carrier Superfamily
Properties of ABC Transporters Related to Drug Action
Table 5-3 The ATP Binding Cassette (ABC) Superfamily in the Human Genome and Linked Genetic Diseases
Table 5-4 ABC Transporters Involved in Drug Absorption, Distribution, and Excretion Processes
GENETIC VARIATION IN MEMBRANE TRANSPORTERS: IMPLICATIONS FOR CLINICAL DRUG RESPONSE
TRANSPORTERS INVOLVED IN PHARMACOKINETICS
Hepatic Transporters
Figure 5-10. Diagram showing hepatic uptake, backflux into blood, metabolism, and efflux into bile. The red circles represent parent drugs; the green triangles represent drug metabolites. PS, permeability surface product; CLmet, metabolic clearance; CLint, intrinsic clearance.
Figure 5-11. Transporters in the hepatocyte that function in the uptake and efflux of drugs across the sinusoidal membrane and efflux of drugs into the bile across the canalicular membrane. See text for details of the transporters pictured.
(Equation 5-13)
Renal Transporters
Figure 5-12. Model of organic cation secretory transporters in the proximal tubule. OC+, organic cation.
Figure 5-13. Model of organic anion secretory transporters in the proximal tubule. OA, organic anion; α-KG, α-ketoglutarate.
TRANSPORTERS INVOLVED IN PHARMACODYNAMICS: DRUG ACTION IN THE BRAIN
BLOOD-BRAIN BARRIER AND BLOOD-CSF BARRIER
BIBLIOGRAPHY
chapter 6 Drug Metabolism
COPING WITH EXPOSURE TO XENOBIOTICS
Figure 6-1. Metabolism of phenytoin by phase 1 cytochrome P450 (CYP) and phase 2 uridine diphosphate-glucuronosyltransferase (UGT). CYP facilitates 4-hydroxylation of phenytoin. The hydroxy group serves as a substrate for UGT that conjugates a molecule of glucuronic acid (in green) using UDP-glucuronic acid (UDP-GA) as a cofactor. This converts a very hydrophobic molecule to a larger hydrophilic derivative that is eliminated via the bile.
THE PHASES OF DRUG METABOLISM
Table 6-1 Xenobiotic Metabolizing Enzymes
SITES OF DRUG METABOLISM
Figure 6-2. Location of CYPs in the cell. The figure shows increasingly microscopic levels of detail, sequentially expanding the areas within the black boxes. CYPs are embedded in the phospholipid bilayer of the endoplasmic reticulum (ER). Most of the enzyme is located on the cytosolic surface of the ER. A second enzyme, NADPH-cytochrome P450 oxidoreductase, transfers electrons to the CYP where it can, in the presence of O2, oxidize xenobiotic substrates, many of which are hydrophobic and dissolved in the ER. A single NADPH-CYP oxidoreductase species transfers electrons to all CYP isoforms in the ER. Each CYP contains a molecule of iron-protoporphyrin IX that functions to bind and activate O2. Substituents on the porphyrin ring are methyl (M), propionyl (P), and vinyl (V) groups.
PHASE 1 REACTIONS
The Cytochrome P-450 Superfamily: the CYPs
Table 6-2 Major Reactions Involved in Drug Metabolism
Figure 6-3. The fraction of clinically used drugs metabolized by the major phase 1 and phase 2 enzymes. The relative size of each pie section represents the estimated percentage of drugs metabolized by the major phase 1 (panel A) and phase 2 (panel B) enzymes, based on studies in the literature. In some cases, more than a single enzyme is responsible for metabolism of a single drug. CYP, cytochrome P450; DPYD, dihydropyrimidine dehydrogenase; GST, glutathione-S-transferase; NAT, Nacetyltransferase; SULT, sulfotransferase, TPMT, thiopurine methyltransferase; UGT, UDP-glucuronosyltransferase.
FLAVIN-CONTAINING MONOOXYGENASES (FMOs)
HYDROLYTIC ENZYMES
Figure 6-4. Metabolism of carbamazepine by CYP and microsomal epoxide hydrolase (mEH). Carbamazepine is oxidized to the pharmacologically-active metabolite carbamazepine-10, 11-epoxide by CYP. The epoxide is converted to a transdihydrodiol by mEH. This metabolite is biologically inactive and can be conjugated by phase 2 enzymes.
CONJUGATING ENZYMES (PHASE 2 REACTIONS)
Figure 6-5. Metabolism of irinotecan (CPT-11). The pro-drug CPT-11 is initially metabolized by a serum esterase (CES2) to the topoisomerase inhibitor SN-38, which is the active camptothecin analog that slows tumor growth. SN-38 is then subject to glucuronidation, which results in loss of biological activity and facilitates elimination of the SN-38 in the bile.
Figure 6-6. Organization of the UGT1A Locus. Transcription of the UGT1A genes commences with the activation of PolII, which is controlled through tissue-specific events. Conserved exons 2–5 are spliced to each respective exon 1 sequence, resulting in the production of unique UGT1A sequences. The UGT1A locus encodes nine functional proteins.
Table 6-3 Drug Toxicity and Gilbert's Syndrome
Figure 6-7. Routes of SN-38 transport and exposure to intestinal epithelial cells. SN-38 is transported into the bile following glucuronidation by liver UGT1A1 and extrahepatic UGT1A7. Following cleavage of luminal SN-38 glucuronide (SN-38G) by bacterial β-glucuronidase, reabsorption into epithelial cells can occur by passive diffusion (indicated by the dashed arrows entering the cell) as well as by apical transporters. Movement into epithelial cells may also occur from the blood by basolateral transporters. Intestinal SN-38 can efflux into the lumen through P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2) and into the blood by means of MRP1. Excessive accumulation of the SN-38 in intestinal epithelial cells and bone marrow, resulting from reduced glucuronidation, can lead to the cellular damage and toxicity depicted in Figure 6-8 (Reproduced with permission from Tukey RH et al. Pharmacogenetics of human UDP-glucuronosyltransferases and irinotecan toxicity. Mol Pharmacol, 2002, 62:446–450. Copyright © 2002 The American Society for Pharmacology and Experimental Therapeutics.).
Figure 6-8. Cellular targets of SN-38 in the blood and intestinal tissues. Excessive accumulation of SN-38 can lead to bone marrow toxicities such as leukopenia and neutropenia, as well as damage to the intestinal epithelium. These toxicities are pronounced in individuals that have reduced capacity to form the SN-38 glucuronide, such as patients with Gilbert's syndrome. Note the different body compartments and cell types involved (Reproduced with permission from Tukey RH et al. Pharmacogenetics of human UDPglucuronosyltransferases and irinotecan toxicity. Mol Pharmacol, 2002, 62:446–450. Copyright © 2002 The American Society for Pharmacology and Experimental Therapeutics.)
Figure 6-9. Glutathione (GSH) as a co-substrate in the conjugation of a drug or xenobiotic (X) by glutathione-S-transferase (GST).
Figure 6-10. Activation of TLK199 by cellular esterases to the glutathione-S-transferase (GST) inhibitor TLK117. (For additional information, see Townsend and Tew, 2003.)
Figure 6-11. Generation of the reactive alkylating agent following the conjugation of glutathione to TLK286. GST interacts with the prodrug and GSH analog, TLK286, via a tyrosine in the active site of GST. GSH portion is shown in red. The interaction promotes β-elimination and cleavage of the prodrug to a vinyl sulfone and an active alkylating fragment. (See Townsend and Tew, 2003.)
Table 6-4 Indications and Unwanted Side Effects of Drug Metabolized by N-Acetyltransferases
ROLE OF XENOBIOTIC METABOLISM IN THE SAFE AND EFFECTIVE USE OF DRUGS
Induction of Drug Metabolism
Table 6-5 Nuclear Receptors That Induce Drug Metabolism
Figure 6-12. Induction of drug metabolism by nuclear receptor-mediated signal transduction. When a drug such as atorvastatin (Ligand) enters the cell, it can bind to a nuclear receptor such as the pregnane X receptor (PXR). PXR then forms a complex with the retinoid X receptor (RXR), binds to DNA upstream of target genes, recruits coactivator (which binds to the TATA box binding protein, TBP), and activates transcription by RNA polymerase II (RNAP II). Among PXR target genes are CYP3A4, which can metabolize the atorvastatin and decrease its cellular concentration. Thus, atorvastatin induces its own metabolism. Atorvastatin undergoes both ortho and para hydroxylation. (See Handschin and Meyer, 2003.)
BIBLIOGRAPHY
chapter 7 Pharmacogenetics
Importance of Pharmacogenetics to Variability in Drug Response
Figure 7-2. Pharmacogenetic contribution to pharmacokinetic parameters. t1/2 of antipyrine is more concordant in identical in comparison to fraternal twin pairs. Bars show the t1/2 of antipyrine in identical (monozygotic) and fraternal (dizygotic) twin pairs. (Redrawn from data in Vesell and Page, 1968.)
GENOMIC BASIS OF PHARMACOGENETICS
Phenotype-Driven Terminology
Figure 7-3. Molecular mechanisms of genetic polymorphisms. The most common genetic variants are single nucleotide polymorphism substitutions (SNPs). Coding non-synonymous SNPs result in a nucleotide substitution that changes the amino acid codon (here proline to glutamine), which could change protein structure, stability, substrate affinities, or introduce a stop codon. Coding synonymous SNPs do not change the amino acid codon, but may have functional consequences (transcript stability, splicing). Noncoding SNPs may be in promoters, introns, or other regulatory regions that may affect transcription factor binding, enhancers, transcript stability, or splicing. The second major type of polymorphism is indels (insertion/deletions). SNP indels can have any of the same effects as SNP substitutions: short repeats in the promoter (which can affect transcript amount), or insertions/deletions that add or subtract amino acids. Copy number variations (CNVs) involve large segments of genomic DNA that may involve gene duplications (stably transmitted inherited germline gene replication that causes increased protein expression and activity), gene deletions that result in the complete lack of protein production, or inversions of genes that may disrupt gene function. All of these mechanisms have been implicated in common germline pharmacogenetic polymorphisms. TPMT, thiopurine methyltransferase; ABCB1, the multidrug resistance transporter (P-glycoprotein); CYP, cytochrome P450; CBS, cystathionine β-synthase; UGT, UDP-glucuronyl transferase; GST, glutathione-S-transferase.
Types of Genetic Variants
Figure 7-4. Nomenclature of genomic regions.
Figure 7-5. Haplotype blocks in UGT1A1 generated by Haploview version 4.1. Linkage disequilibrium between SNPs in UGT1A1 in Europeans is shown. SNPs present at allele frequencies of 20% or greater are included and identified by rs numbers. The r2 values indicating linkage disequilibrium values between any two SNPs are shown in the blocks below as whole numbers (e.g., 86 = r2 of 0.86 between SNPs at rs4148238 and rs8330. Those that are dark blue without numbers have an r2 = 1.0. The relationships among the SNP genotypes in this population for this gene indicate that there are three primary linkage disequilibrium blocks (Block 1, Block 2, and Block 3), which in this case, were generated by the Haploview program. (Source: Broad Institute, http://www.broad.mit.edu/haploview/haploview.)
Ethnic Diversity
Figure 7-6. Coding region polymorphisms in two membrane transporters. Shown are the dopamine transporter, DAT (encoded by SLC6A3) and multidrug resistance associated protein, MRP2 (encoded by ABCC2). Coding region variants were identified in 247 ethnically diverse DNA samples (100 African Americans, 100 European Americans, 30 Asians, 10 Mexicans, and 7 Pacific islanders). Shown in blue circles are synonymous variants, and in red circles, non-synonymous variants.
Polymorphism Selection
PHARMACOGENETIC STUDY DESIGN CONSIDERATIONS
Pharmacogenetic Measures
Figure 7-7. Monogenic versus multigenic pharmacogenetic traits. Possible alleles for a monogenic trait (upper left), in which a single gene has a low-activity (1a) and a high-activity (1b) allele. The population frequency distribution of a monogenic trait (bottom left), here depicted as enzyme activity, may exhibit a trimodal frequency distribution with relatively distinct separation among low activity (homozygosity for 1a), intermediate activity (heterozygote for 1a and 1b), and high activity (homozygosity for 1b). This is contrasted with multigenic traits (e.g., ivity influenced by up to four different genes, genes 2 through 5), each of which has 2, 3, or 4 alleles (a through d). The population histogram for activity is unimodal-skewed, with no distinct differences among the genotypic groups. Multiple combinations of alleles coding for low activity and high activity at several of the genes can translate into low-, medium-, and high-activity phenotypes.
Candidate Gene Versus Genome-Wide Approaches
Table 7-1 Databases Containing Information on Human Genetic Variation
Functional Studies of Polymorphisms
Table 7-2 Predicted Functional Effect and Relative Risk That a Variant Will Alter Function of SNP Types in the Human Genome
Figure 7-8. Functional activity of natural variants of two membrane transporters. Data for the organic cation transporter (OCT1, top panel) and the nucleoside transporter (CNT3, bottom panel). Variants, identified in ethnically diverse populations, were constructed by site-directed mutagenesis and expressed in Xenopus laevis oocytes. Blue bars represent uptake of the model compounds by variant transporters. Red bars represent uptake of the model compounds by reference transporters. MPP+, 1-methyl-4-phenylpyridium. (Reproduced with permission from Shu et al., 2003. Copyright © National Academy of Sciences, USA.)
Figure 7-9. Simulated concentration-dependence curves showing the rate of metabolism of a hypothetical substrate by the common genetic form of an enzyme and two non-synonymous variants. Variant A exhibits an increased Km and likely reflects a change in the substrate binding site of the protein by the substituted amino acid. Variant B exhibits a change in the maximum rate of metabolism (Vmax) of the substrate. This may be due to reduced expression level of the enzyme.
Pharmacogenetic Phenotypes
Figure 7-10. Types of genetic variants that have been significantly associated with complex human traits and disease in 208 genomewide association studies. Approximately 500 SNPs were associated with human disease and complex traits. Intergenic and intronic SNPs comprise the largest fraction of associated variants. See www.genome.gov/gwastudies/.
Figure 7-11. An intronic SNP can affect splicing and account for polymorphic expression of CYP3A5. A common polymorphism (A>G) in intron 3 of CYP3A5 defines the genotypes associated with the wild-type CYP3A5*1 allele, or the variant nonfunctional CYP3A5*3 allele. This intronic SNP creates an alternative splice site that results in the production of an alternative CYP3A5 transcript carrying an additional intron 3B (panel B), with an accompanying early stop codon and truncated CYP3A5 protein. Whereas the wild-type gene (more common in African than Caucasian or Asian populations) results in production of active CYP3A5 protein (panel A), the *3 variant results in a truncated and inactive CYP3A5 protein. Thus, metabolism of CYP3A5 substrates is diminished in vitro (panel C, shown for midazolam) and blood concentrations of such medications are higher in vivo (panel D, shown for tacrolimus) for these with the *3 than the *1 allele. (Based on data from Haufroid et al., 2004; Kuehl et al., 2001; Lin et al., 2002.)
Table 7-3 Examples of Genetic Polymorphisms Influencing Drug Response
Figure 7-12. Effect of CYP2C19 genotype on proton pump inhibitor (PPI) pharmacokinetics (AUC), gastric pH, and ulcer cure rates. Depicted are the average variables for CYP2C19 homozygous extensive metabolizers (homEM), heterozygotes (hetEM), and poor metabolizers (PM). (Reproduced with permission from Furuta T et al. Pharmcogenomics of proton pump inhibitors. Pharmacogenomics, 2004, 5: 181–202. Copyright © 2004 Future Medicine Ltd. All rights reserved.)
Figure 7-13. Pharmacogenetics of warfarin dosing. Warfarin is metabolized by CYP2C9 to inactive metabolites, and exerts its anticoagulant effect partly via inhibition of VKORC1 (vitamin K epoxide hydrolase), an enzyme necessary for reduction of inactive to active vitamin K. Common polymorphisms in both genes, CYP2C9 and VKORC1, impact on warfarin pharmacokinetics and pharmacodynamics, respectively, to affect the population mean therapeutic doses of warfarin necessary to maintain the desired degree of anticoagulation (often measured by the international normalized ratio [INR] blood test) and minimize the risk of too little anticoagulation (thrombosis) or too much anticoagulation (bleeding). (Based on data from Caraco et al., 2008; Schwarz et al., 2008; Wen et al., 2008.)
Pharmacogenetics and Drug Development
Pharmacogenetics in Clinical Practice
Figure 7-14. Three primary types of evidence in pharmacogenetics. Screens of human tissue (A) link phenotype (thiopurine methyltransferase activity in erythrocytes) with genotype (germline TPMT genotype). The two alleles are separated by a slash (/); the *1 and *1S alleles are wild-type, and the *2, *3A, and *3C are nonfunctional alleles. Shaded areas indicate low and intermediate levels of enzyme activity: those with the homozygous wild-type genotype have the highest activity, those heterozygous for at least one *1 allele have intermediate activity, and those homozygous for two inactive alleles have low or undetectable TPMT activity (Yates et al., 1997). Directed preclinical functional studies (B) can provide biochemical data consistent with the in vitro screens of human tissue, and may offer further confirmatory evidence. Here, the heterologous expression of the TPMT*1 wild-type and the TPMT*2 variant alleles indicate that the former produces a more stable protein, as assessed by Western blot (Tai et al., 1997). The third type of evidence comes from clinical phenotype/genotype association studies (C and D). The incidence of required dosage decrease for thiopurine in children with leukemia (C) differs by TPMT genotype: 100%, 35%, and 7% of patients with homozygous variant, heterozygous, or homozygous wild-type, respectively, require a dosage decrease (Relling et al., 1999). When dosages of thiopurine are adjusted based on TPMT genotype in the successor study (D), leukemic relapse is not compromised, as indicated by comparable relapse rates in children who were wild-type vs. heterozygous for TPMT. Taken together, these three data sets indicate that the polymorphism should be accounted for in dosing of thiopurines. (Reproduced with permission from Relling et al., 1999. Copyright © Oxford University Press.)
BIBLIOGRAPHY
Section II Neuropharmacology
chapter 8 Neurotransmission: The Autonomic and Somatic Motor Nervous Systems
ANATOMY AND GENERAL FUNCTIONS
Figure 8-1. The autonomic nervous system. Schematic representation of the autonomic nerves and effector organs based on chemical mediation of nerve impulses. Yellow, cholinergic; red, adrenergic; dotted blue, visceral afferent; solid lines, preganglionic; broken lines, postganglionic. In the upper rectangle at the right are shown the finer details of the ramifications of adrenergic fibers at any one segment of the spinal cord, the path of the visceral afferent nerves, the cholinergic nature of somatic motor nerves to skeletal muscle, and the presumed cholinergic nature of the vasodilator fibers in the dorsal roots of the spinal nerves. The asterisk (*) indicates that it is not known whether these vasodilator fibers are motor or sensory or where their cell bodies are situated.
Figure 8-2. Schematic representation of the somatic motor nerves and the efferent nerves of the autonomic nervous system. The principal neurotransmitters, acetylcholine(ACh) and norepinephrine (NE), are shown in red. The receptors for these transmitters, nicotinic (N) and muscarinic (M) cholinergic receptors, α and β adrenergic receptors, are shown in green. The somatic nerves innervate skeletal muscle directly without a ganglionic relay. The autonomic nerves innervate smooth muscles, cardiac tissue and glands. Both parasympathetic and sympathetic systems have ganglia where ACh is the transmitter of the preganglionic fibers; ACh acts on nicotinic receptors on the postganglionic nerves. ACh is also the neurotransmitter at cells of the adrenal medulla, where it acts on nicotinic ACh receptors to cause release of the catecholamines epinephrine (Epi) and NE into the circulation. Epi represents ~80% of the released catecholamines. ACh is the predominant neurotransmitter of postganglionic parasympathetic nerves and acts on muscarinic receptors. NE is the principal neurotransmitter of postganglionic sympathetic nerves, acting on α or β adrenergic receptors. Note that somatic nerves form a specialized synaptic junction, termed the motor end plate. Autonomic nerves form a more diffuse pattern with multiple synaptic sites. The ganglia in the parasympathetic system are near or within the organ being innervated with generally a one-to-one relationship between pre- and post-ganglionic fibers. In the sympathetic system the ganglia are generally far from the effector cells (e.g., within the sympathetic chain ganglia). Preganglionic sympathetic fibers may make contact with a large number of postganglionic fibers.
Table 8-1 Responses of Effector Organs to Autonomic Nerve Impulses
NEUROTRANSMISSION
Evidence for Neurohumoral Transmission
Steps Involved in Neurotransmission
Figure 8-3. Steps involved in excitatory and inhibitory neurotransmission. 1. The nerve action potential (AP) consists of a transient selfpropagated reversal of charge on the axonal membrane. (The internal potential Ei goes from a negative value, through zero potential, to a slightly positive value primarily through increases in Na+ permeability and then returns to resting values by an increase in K+ permeability.) When the AP arrives at the presynaptic terminal, it initiates release of the excitatory or inhibitory transmitter. Depolarization at the nerve ending and entry of Ca2+ initiate docking and then fusion of the synaptic vesicle with the membrane of the nerve ending. Docked and fused vesicles are shown. 2. Combination of the excitatory transmitter with postsynaptic receptors produces a localized depolarization, the excitatory postsynaptic potential (EPSP), through an increase in permeability to cations, most notably Na+. The inhibitory transmitter causes a selective increase in permeability to K+ or Cl-, resulting in a localized hyperpolarization, the inhibitory postsynaptic potential (IPSP). 3. The EPSP initiates a conducted AP in the postsynaptic neuron; this can be prevented, however, by the hyperpolarization induced by a concurrent IPSP. The transmitter is dissipated by enzymatic destruction, by reuptake into the presynaptic terminal or adjacent glial cells, or by diffusion. Depolarization of the postsynaptic membrane can permit Ca2+ entry if voltage-gated Ca2+ channels are present. (Reproduced with permission from Brunton L, Parker K, Blumenthal D, Buxton I (eds). Goodman & Gilman's Manual of Pharmacology and Therapeutics. New York: McGraw-Hill, 2008, p 94. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.)
Cholinergic Transmission
Figure 8-4. A cholinergic neuroeffector junction showing features of the synthesis, storage, and release of acetylcholine (ACh) and receptors on which ACh acts. The synthesis of ACh in the varicosity depends on the uptake of choline via a sodium-dependent carrier. This uptake can be blocked by hemicholinium. Choline and the acetyl moiety of acetyl coenzyme A, derived from mitochondria, form ACh, a process catalyzed by the enzyme choline acetyl transferase (ChAT). ACh is transported into the storage vesicle by another carrier that can be inhibited by vesamicol. ACh is stored in vesicles along with other potential cotransmitters (Co-T) such as ATP and VIP at certain neuroeffector junctions. Release of ACh and the Co-T occurs on depolarization of the varicosity, which allows the entry of Ca2+ through voltage-dependent Ca2+ channels. Elevated [Ca2+]in promotes fusion of the vesicular membrane with the cell membrane, and exocytosis of the transmitters occurs. This fusion process involves the interaction of specialized proteins associated with the vesicular membrane (VAMPs, vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associated proteins). The exocytotic release of ACh can be blocked by botulinum toxin. Once released, ACh can interact with the muscarinic receptors (M), which are GPCRs, or nicotinic receptors (N), which are ligand-gated ion channels, to produce the characteristic response of the effector. ACh also can act on presynaptic mAChRs or nAChRs to modify its own release. The action of ACh is terminated by metabolism to choline and acetate by acetylcholinesterase (AChE), which is associated with synaptic membranes.
Cholinergic Receptors and Signal Transduction
Table 8-2 Characteristics of Subtypes of Nicotinic Acetylcholine Receptors (nAChRs)
Table 8-3 Characteristics of Subtypes of Nicotinic Acetylcholine Receptors (nAChRs)
Adrenergic Transmission
Figure 8-5. Steps in the enzymatic synthesis of dopamine, norepinephrine and epinephrine. The enzymes involved are shown in red; essential cofactors in italics. The final step occurs only in the adrenal medulla and in a few epinephrine-containing neuronal pathways in the brainstem.
Table 8-4 Enzymes for Synthesis of Catecholamines
Figure 8-6. An adrenergic neuroeffector junction showing features of the synthesis, storage, release, and receptors for norepinephrine (NE), the cotransmitters neuropeptide Y (NPY), and ATP. Tyrosine is transported into the varicosity and is converted to DOPA by tyrosine hydroxylase (TH) and DOPA to dopamine (DA) by the action of aromatic L-amino acid decarboxylase (AAADC). Dopamine is taken up into the vesicles of the varicosity by a transporter, VMAT2, that can be blocked by reserpine. Cytoplasmic NE also can be taken up by this transporter. Dopamine is converted to NE within the vesicle via the action of dopamine-β-hydroxylase (DβH). NE is stored in vesicles along with other cotransmitters, NPY and ATP, depending on the particular neuroeffector junction. Release of the transmitters occurs upon depolarization of the varicosity, which allows entry of Ca2+ through voltage-dependent Ca2+ channels. Elevated levels of Ca2+ promote the fusion of the vesicular membrane with the membrane of the varicosity, with subsequent exocytosis of transmitters. This fusion process involves the interaction of specialized proteins associated with the vesicular membrane (VAMPs, vesicle-associated membrane proteins) and the membrane of the varicosity (SNAPs, synaptosome-associated proteins). In this schematic representation, NE, NPY, and ATP are stored in the same vesicles. Different populations of vesicles, however, may preferentially store different proportions of the cotransmitters. Once in the synapse, NE can interact with α and β adrenergic receptors to produce the characteristic response of the effector. The adrenergic receptors are GPCRs. α and β Receptors also can be located presynaptically where NE can either diminish (α2), or facilitate (β) its own release and that of the cotransmitters. The principal mechanism by which NE is cleared from the synapse is via a cocaine-sensitive neuronal uptake transporter, NET. Once transported into the cytosol, NE can be re-stored in the vesicle or metabolized by monoamine oxidase (MAO). NPY produces its effects by activating NPY receptors, of which there are at least five types (Y1 through Y2). NPY receptors are GPCRs. NPY can modify its own release and that of the other transmitters via presynaptic receptors of the Y2 type. NPY is removed from the synapse by metabolic breakdown by peptidases. ATP produces its effects by activating P2X receptors or P2Y receptors. P2X receptors are ligand-gated ion channels; P2Y receptors are GPCRs. There are multiple subtypes of both P2X and P2Y receptors. As with the other cotransmitters, ATP can act prejunctionally to modify its own release via receptors for ATP or via its metabolic breakdown to adenosine that acts on P1 (adenosine) receptors. ATP is cleared from the synapse primarily by releasable nucleotidases (rNTPase) and by cell-fixed ectonucleotidases.
Table 8-5 Characteristics of Plasma Membrane Transporters for Endogenous Catecholamines
Figure 8-7. Steps in the metabolic disposition of catecholamines. Norepinephrine and epinephrine are first oxidatively deaminated to a short lived intermediate (DOPGAL) by monoamine oxidase (MAO). DOPGAL then undergoes further metabolism to more stable alcohol or acid deaminated metabolites. Aldehyde dehydrogenase (AD) metabolizes DOPGAL to 3,4-dihydroxymandelic acid (DOMA) while aldehyde reductase (AR) metabolizes DOPGAL to 3,4-dihydroxyphenyl glycol (DOPEG). Under normal circumstances DOMA is a minor metabolite with DOPEG being the major metabolite produced from norepinephrine and epinephrine. Once DOPEG leaves the major sites of its formation (sympathetic nerves; adrenal medulla), it is converted to 3-methoxy, 4-hydroxyphenylglycol (MOPEG) by catechol-0-methyl transferase (COMT). MOPEG is then converted to the unstable aldehyde (MOPGAL) by alcohol dehydrogenase (ADH) and finally to vanillyl mandelic acid (VMA) by aldehyde dehydrogenase. VMA is the major end product of norepinephrine and epinephrine metabolism. Another route for the formation of VMA is conversion of norepinephrine or epinephrine into normetanephrine or metanephrine by COMT either in the adreneal medulla or extraneuronal sites,with subsequent metabolism to MOPGAL and thence to VMA.
Table 8-6 Characteristics for Adrenergic Receptor Subtypes
Table 8-6 Characteristics for Adrenergic Receptor Subtypes(Continued)
Table 8-7 Representative Agents Acting at Peripheral Cholinergic and Adrenergic Neuroeffector Junctions
Figure 8-8. Subtypes of adrenergic receptors. All of the adrenergic receptors are heptaspanning GPCRs. A representative of each type is shown; each type has three subtypes: α1A, α1B, and α1D; α2A, α2B, and α2C; and β1, β2, and β3. The principle effector systems affected by α1, α2 and β receptors are depicted in Table 8-6. (Ψ) indicates a site for N-glycosylation. indicates a site for thio-acetylation.
RELATIONSHIP BETWEEN THE NERVOUS AND ENDOCRINE SYSTEMS
PHARMACOLOGICAL CONSIDERATIONS
Interference with the Synthesis or Release of the Transmitter
Promotion of Release of the Transmitter
Agonist and Antagonist Actions at Receptors
Interference with the Destruction of the Transmitter
OTHER AUTONOMIC NEUROTRANSMITTERS
BIBLIOGRAPHY
chapter 9 Muscarinic Receptor Agonists and Antagonists
ACETYLCHOLINE AND ITS MUSCARINIC RECEPTOR TARGET
Properties and Subtypes of Muscarinic Receptors
Pharmacological Effects of Acetylcholine
Figure 9-1. Structural formulas of acetylcholine, choline esters, and natural alkaloids that stimulate muscarinic receptors.
MUSCARINIC RECEPTOR AGONISTS
Table 9-1 Some Pharmacological Properties of Choline Esters and Natural Alkaloids
Absorption, Distribution, and Elimination
Therapeutic Uses of Muscarinic Receptor Agonists
Contraindications, Precautions, and Adverse Effects
Toxicology
MUSCARINIC RECEPTOR ANTAGONISTS
Table 9-2 Effects of Atropine in Relation to Dose
Figure 9-2. Structural formulas of the belladonna alkaloids and semisynthetic and synthetic analogs. The red C identifies an asymmetric carbon atom.
Pharmacological Effects of Muscarinic Antagonists
Cardiovascular System
Other Smooth Muscle
Ipratropium and Tiotropium
Therapeutic Uses of Muscarinic Receptor Antagonists
Table 9-3 Muscarinic Receptor Antagonists Used in the Treatment of Overactive Urinary Bladder
Contraindications and Adverse Effects
Toxicology of Drugs with Antimuscarinic Properties
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 10 Anticholinesterase Agents
Figure 10-1. The active center gorge of mammalian acetylcholinesterase. Bound acetylcholine is shown by the dotted structure depicting its van der Waals radii. The crystal structure of mouse cholinesterase active center, which is virtually identical to human AChE, is shown (Bourne et al., 1995). Included are the side chains of (a) the catalytic triad, Glu334, His447, Ser203 (hydrogen bonds are denoted by the dotted lines); (b) acyl pocket, Phe295 and Phe297; (c) choline subsite, Trp86, Glu202, and Tyr337; and (d) the peripheral site: Trp286, Tyr72, Tyr124, and Asp74. Tyrosines 337 and 449 are further removed from the active center but likely contribute to stabilization of certain ligands. The catalytic triad, choline subsite, and acyl pocket are located at the base of the gorge, while the peripheral site is at the lip of the gorge. The gorge is 18–20 Å deep, with its base centrosymmetric to the subunit.
Figure 10-2. Steps involved in the hydrolysis of acetylcholine by acetylcholinesterase and in the inhibition and reactivation of the enzyme. Only the three residues of the catalytic triad shown in Figure 10-1 are depicted. The associations and reactions shown are: A. Acetylcholine (ACh) catalysis: binding of ACh, formation of a tetrahedral transition state, formation of the acetyl enzyme with liberation of choline, rapid hydrolysis of the acetyl enzyme with return to the original state. B. Reversible binding and inhibition by edrophonium. C. Neostigmine reaction with and inhibition of AChE: reversible binding of neostigmine, formation of the dimethyl carbamoyl enzyme, slow hydrolysis of the dimethyl carbamoyl enzyme. D. Diisopropyl fluorophosphate (DFP) reaction and inhibition of AChE: reversible binding of DFP, formation of the diisopropyl phosphoryl enzyme, formation of the aged monoisopropyl phosphoryl enzyme. Hydrolysis of the diisopropyl enzyme is very slow and is not shown. The aged monoisopropyl phosphoryl enzyme is virtually resistant to hydrolysis and reactivation. The tetrahedral transition state of ACh hydrolysis resembles the conjugates formed by the tetrahedral phosphate inhibitors and accounts for their potency. Amide bond hydrogens from Gly121 and Gly122 stabilize the carbonyl and phorphoryl oxygens. E. Reactivation of the diisopropyl phosphoryl enzyme by pralidoxime (2-PAM). 2-PAM attack of the phosphorus on the phosphorylated enzyme will form a phospho-oxime with regeneration of active enzyme. The individual steps of phosphorylation reaction and oxime reaction have been characterized by mass spectrometry (Jennings et al., 2003).
CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIPS
Figure 10-3. Representative "reversible" anticholinesterase agents employed clinically.
Table 10-1 Chemical Classification of Representative Organophosphorus Compounds of Particular Pharmacological or Toxicological Interest
PHARMACOLOGICAL PROPERTIES
TOXICOLOGY
THERAPEUTIC USES
BIBLIOGRAPHY
chapter 11 Agents Acting at the Neuromuscular Junction and Autonomic Ganglia
THE NICOTINIC ACETYLCHOLINE RECEPTOR
Figure 11-1. Subunit organization of pentameric ligand-gated ion channels and the ACh binding protein. For each receptor, the amino terminal region of ~ 210 amino acids is found at the extracellular surface. It is then followed by four hydrophobic regions that span the membrane (TM1-TM4), leaving the small carboxyl terminus on the extracellular surface. The TM2 region is α-helical, and TM2 regions from each subunit of the pentameric receptor line the internal pore of the receptor. Two disulfide loops at positions 128–142 and 192–193 are found in the α-subunit of the nicotinic receptor. The 128–142 motif is conserved in the family of receptors, whereas the vicinal cysteines at 192 and 193 distinguish α- subunits and the acetylcholine binding protein from β, γ, δ, and ɛ?in the nicotinic receptor.
Figure 11-2. Subunit arrangement and molecular structure of the nicotinic acetylcholine receptor. A. Longitudinal view of receptor schematic with the γ subunit removed. The remaining subunits, two copies of α, one of β, and one of δ, are shown to surround an internal channel with an outer vestibule and its constriction located deep in the membrane bilayer region. Spans of α-helices with slightly bowed structures form the perimeter of the channel and come from the TM2 region of the linear sequence (Figure 11-1). Acetylcholine (ACh) binding sites, indicated by arrows, are found at the αγ and αδ (not visible) interfaces. B. Longitudinal view of the receptor from Torpedo showing secondary structure and membrane topology from 4 Å electron micrograph data (Unwin, 2005). The ACh binding protein (panel C) is homologous to the extracellular domain of the nicotinic receptor (Figure 11-1). The protein is a homopentamer that binds nicotinic receptor ligands with the expected selectivity and, when fused to the TM portions of the receptor, yields a functional ligand-gated channel. The subunit structure of the ACh binding protein is clear from the top view (panel C, upper orientation) and side view (panel C, lower orientation). The agonist nicotine is shown bound to the ACh binding protein with its atoms modeled as spheres in C. Nicotinic receptor subunit arrangement is shown in D, with examples of subunit assembly and location of agonist binding sites (small red circles) at α?subunit-containing interfaces in nicotinic receptors. A total of 17 functional receptor isoforms have been observed in vivo, with different ligand specificity, relative Ca2+/Na+ permeability, and physiological function as determined by their subunit composition. The only isoform found at the neuromuscular junction (and in the electric organ of Torpedo) is that shown here. The 16 neuronal receptor isoforms, found at autonomic ganglia and in the central nervous system, form homo- and heteropentameric nicotinic receptors composed of α2-α10 and β2-β4 subunits.
NEUROMUSCULAR BLOCKING AGENTS
Pharmacological Properties
Actions on Organ Systems
Figure 11-3. Structural formulas of major neuromuscular blocking agents.
Table 11-1 Clinical Responses and Monitoring of Phase I and Phase II Neuromuscular Blockade by Succinylcholine Infusion
Figure 11-4. Sites of action of agents at the neuromuscular junction and adjacent structures. The anatomy of the motor end plate, shown at the left, and the sequence of events from liberation of acetylcholine (ACh) by the nerve action potential (AP) to contraction of the muscle fiber, indicated by the middle column, are described in Chapter 8. The modification of these processes by various agents is shown on the right; an arrow marked with an X indicates inhibition or block; an unmarked arrow indicates enhancement or activation. The insets are enlargements of the indicated structures. The highest magnification depicts the receptor in the bilayer of the postsynaptic membrane. A more detailed view of the receptor is shown in Figure 11-2.
Absorption, Distribution, and Elimination
Clinical Pharmacology
Choice of Agent
Table 11-2 Classification of Neuromuscular Blocking Agents
Table 11-3 Dosing Ranges for Neuromuscular Blocking Agents
Clinical Uses
Table 11-4 Comparison of Competitive (d-Tubocurarine) and Depolarizing (Decamethonium) Blocking Agents
Toxicology
GANGLIONIC NEUROTRANSMISSION
Figure 11-5. Postsynaptic potentials recorded from an autonomic postganglionic nerve cell body after stimulation of the preganglionic nerve fiber. The preganglionic nerve releases ACh onto postganglionic cells. The initial EPSP results from the inward Na+ current (and perhaps Ca2+ current) through the nicotinic receptor channel. If the EPSP is of sufficient magnitude, it triggers an action potential spike, which is followed by a slow IPSP, a slow EPSP, and a late, slow EPSP. The slow IPSP and slow EPSP are not seen in all ganglia. The electrical events subsequent to the initial EPSP are thought to modulate the probability that a subsequent EPSP will reach the threshold for triggering a spike. Other interneurons, such as catecholamine-containing, small, intensely fluorescent (SIF) cells, and axon terminals from sensory, afferent neurons also release transmitters and that may influence the slow potentials of the postganglionic neuron. A number of cholinergic, peptidergic, adrenergic, and amino acid receptors are found on the dendrites and soma of the postganglionic neuron and the interneurons. The preganglionic fiber releases ACh and peptides; the interneurons store and release catecholamines, amino acids, and peptides; the sensory afferent nerve terminals release peptides. The initial EPSP is mediated through nicotinic (Nn) receptors, the slow IPSP and EPSP through M2 and M1 muscarinic receptors, and the late, slow EPSP through several types of peptidergic receptors.
GANGLIONIC STIMULATING DRUGS
Figure 11-6. Ganglionic stimulants.
Nicotine
GANGLIONIC BLOCKING DRUGS
Figure 11-7. Ganglionic blocking agents.
Table 11-5 Usual Predominance of Sympathetic or Parasympathetic Tone at Various Effector Sites, and Consequences of Autonomic Ganglionic Blockade
Clinical Summary
BIBLIOGRAPHY
chapter 12 Adrenergic Agonists and Antagonists
Catecholamines and Sympathomimetic Drugs
CLASSIFICATION OF SYMPATHOMIMETIC DRUGS
Figure 12-1. Classification of adrenergic receptor agonists (sympathomimetic amines) or drugs that produce sympathomimetic-like effects. For each category, a prototypical drug is shown. (*Not actually sympathetic drugs but produce sympathomimetic-like effects.)
Table 12-1 Chemical Structures and Main Clinical Uses of Important Sympathomimetic Drugsb
ENDOGENOUS CATECHOLAMINES
Epinephrine
Figure 12-2. Effects of intravenous infusion of norepinephrine, epinephrine or isoproterenol in humans. (Modified from Allwood et al., 1963, with permission from Oxford University Press.)
Table 12-2 Comparison of the Effects of Infusion of Epinephrine and Norepinephrine in Human Beingsa
Norepinephrine
Dopamine
Pharmacological Properties.
β ADRENERGIC RECEPTOR AGONISTS
Isoproterenol
Dobutamine
β2-Selective Adrenergic Receptor Agonists
Short Acting β2 Adrenergic Agonists
Figure 12-3. Structural formulas of some β2 adrenergic receptor agonists.
Long-Acting β2 Adrenergic Agonists
α1-SELECTIVE ADRENERGIC RECEPTOR AGONISTS
Phenylephrine
α2-SELECTIVE ADRENERGIC RECEPTOR AGONISTS
Clonidine
MISCELLANEOUS SYMPATHOMIMETIC AGONISTS
Amphetamine
Methamphetamine
Methylphenidate
Ephedrine
Figure 12-4. Chemical structures of imidazoline derivatives.
Other Sympathomimetic Agents
THERAPEUTIC USES OF SYMPATHOMIMETIC DRUGS
Adrenergic Receptor Antagonists
Figure 12-5. Classification of adrenergic receptor antagonists. Drugs marked by an asterisk (*) also block α1 receptors.
α ADRENERGIC RECEPTOR ANTAGONISTS
α1 Receptor Antagonists
Available Agents
Figure 12-6. Structural formulas of some α adrenergic receptor antagonists.
Therapeutic Uses
α2 ADRENERGIC RECEPTOR ANTAGONISTS
Additional α Adrenergic Receptor Antagonists
β ADRENERGIC RECEPTOR ANTAGONISTS
Figure 12-7. Structural formulas of some β adrenergic receptor antagonists
Figure 12-8. Structural formulas of some "third-generation" β adrenergic receptor antagonists with additional cardiovascular effects.
Pharmacological Properties
Table 12-3 Pharmacological/Pharmacokinetic Properties of β Adrenergic Receptor Blocking Agents
Table 12-4 Third Generation β Receptor Antagonists with Putative Additional Mechanisms of Vasodilation
Figure 12-9. Mechanisms underlying actions of vasodilating β blockers in blood vessels. ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; AC adenylyl cyclase; L-type VGCC, L-type voltage gated Ca2+ channel.) (Modified with permission from Toda, 2003. Copyright © Elsevier.)
ADVERSE EFFECTS AND PRECAUTIONS
THERAPEUTIC USES
Cardiovascular Diseases
CLINICAL USE OF β ADRENERGIC RECEPTOR ANTAGONISTS
NON-SELECTIVE β ADRENERGIC RECEPTOR ANTAGONISTS
Propranolol
Nadolol
Table 12-5 Summary of Adrenergic Agonists and Antagonists
Timolol
Pindolol
β1 SELECTIVE ADRENERGIC RECEPTOR ANTAGONISTS
Metoprolol
Atenolol
Esmolol
Acebutolol
Bisoprolol
Betaxolol
β RECEPTOR ANTAGONISTS WITH ADDITIONAL CARDIOVASCULAR EFFECTS ("THIRD GENERATION" β BLOCKERS)
Labetalol
Carvedilol
Bucindolol
Celiprolol
Nebivolol
BIBLIOGRAPHY
chapter 13 5-Hydroxytryptamine (Serotonin) and Dopamine
5-HYDROXYTRYPTAMINE
Figure 13-1. Structures of representative indolealkylamines.
Figure 13-2. Synthesis and inactivation of serotonin. Enzymes are identified in red lettering, and co-factors are shown in blue.
PHYSIOLOGICAL FUNCTIONS OF SEROTONIN
Multiple 5-HT Receptors
Table 13-1 Serotonin Receptor Subtypes
Table 13-2 Physiological Roles of 5-HT Receptors Defined by Phenotypes in Knockout Mice
Figure 13-3. Two classes of 5-HT autoreceptors with differential localizations. Somatodendritic 5-HT1A autoreceptors decrease raphe cell firing when activated by 5-HT released from axon collaterals of the same or adjacent neurons. The receptor subtype of the presynaptic autoreceptor on axon terminals in the forebrain has different pharmacological properties and has been classified as 5-HT1D (in humans) or 5-HT1B (in rodents). This receptor modulates the release of 5-HT. Postsynaptic 5-HT1 receptors are also indicated.
Actions of 5-HT in Physiological Systems
Figure 13-4. Schematic representation of the local influences of platelet 5-HT. The release of 5-HT stored in platelets is triggered by aggregation. The local actions of 5-HT include feedback actions on platelets (shape change and accelerated aggregation) mediated by interaction with platelet 5-HT2A receptors, stimulation of NO production mediated by 5-HT1-like receptors on vascular endothelium, and contraction of vascular smooth muscle mediated by 5-HT2A receptors. These influences act in concert with many other mediators that are not shown to promote thrombus formation and hemostasis. See Chapter 30 for details of adhesion and aggregation of platelets and factors contributing to thrombus formation and blood clotting.
Table 13-3 Some Actions of 5-HT in the Gastrointestinal Tract
Table 13-4 Electrophysiological Effects of 5-HT Receptors
Pharmacological Manipulation of the Amount of 5-HT in Tissues
5-HT RECEPTOR AGONISTS AND ANTAGONISTS
5-HT Receptor Agonists
Table 13-5 Serotonergic Drugs: Primary Actions and Clinical Indications
5-HT1 Receptor Agonists
Figure 13-5. Structures of representative triptans (selective 5-HT1 receptor agonists).
Table 13-6 Natural and Semisynthetic Ergot Alkaloids
5-HT Receptor Antagonists
Clinical Manipulation of 5-HT Levels: Serotonin Syndrome
DOPAMINE
Figure 13-6. Synthesis and inactivation of dopamine. Enzymes are identified in blue lettering, and co-factors are shown in black letters.
Figure 13-7. Dopaminergic nerve terminal. Dopamine (DA) is synthesized from tyrosine in the nerve terminal by the sequential actions of tyrosine hydrolase (TH) and aromatic amino acid decarboxylase (AADC). DA is sequestered by VMAT2 in storage granules and released by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2 receptors. Synaptic DA may be taken up into the neuron via the DA and NE transporters (DAT, NET), or removed by postsynaptic uptake via OCT3 transporters. Cytosolic DA is subject to degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the neuron, and by catechol-O-methyl tranferase (COMT) and MAO/ALDH in non-neuronal cells; the final metabolic product is homovanillic acid (HVA). See structures in Figure 13-6. PH, phenylalanine hydroxylase.
PHYSIOLOGICAL FUNCTIONS OF DOPAMINE
Multiple DA Receptors
Figure 13-8. Distribution and characterization of DA receptors in the CNS.
Actions of DA on Physiologic Systems
Figure 13-9. Major DA pathways in brain.
Roles of DA in Behavior: Lesioning and Knockout Studies
DA Receptor Agonists and Antagonists
Table 13-7 Experimental Tools at DA Receptors
DA Receptor Antagonists
Antipsychotic Agents
BIBLIOGRAPHY
chapter 14 Neurotransmission and the Central Nervous System
ORGANIZATIONAL PRINCIPLES OF THE CNS
Microanatomy of the Brain
Figure 14-1. Principal features of a typical vertebrate neuron. Dendrites, including apical dendrites, receive synapses from presynaptic terminals. The cell body contains the nucleus and is the site of transcription and translation. The axon carries information from the perikaryon to the presynaptic terminals, which form synapses with the dendrites of other neurons. Axo-somatic synapses also occur. Many CNS-active pharmacological agents act at the presynaptic and postsynaptic membranes of the synaptic clefts, and at areas of transmitter storage near the synapses. (Adapted with permission from Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neuroscience, 4th ed. New York: McGraw-Hill, 2000, p 22. Copyright © 2000 by The McGraw-Hill Companies, Inc. All rights reserved.)
Response to Damage: Repair and Plasticity in the CNS
INTEGRATIVE CHEMICAL COMMUNICATION IN THE CNS
Figure 14-2. Structural similarities of voltage-dependent Na+, Ca2+ and K+ channels. A. The α subunit in both Ca2+ and Na+ channels contains four subunits, each with six transmembrane hydrophobic domains. The hydrophobic regions that connect segments five and six in each domain form the pore of the channel. Segment four in each domain includes the voltage-sensor. See Figure 20-2 for additional details. (Adapted with permission from Catterall W. From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron, 2000, 26:13–25. Copyright © Elsevier.) B. The Ca2+ channel also requires several auxiliary small proteins (α2, β, γ, and δ). The α2 and δ subunits are linked by a disulfide bond. Regulatory subunits also exist for Na+ channels. C. Voltage-sensitive K+ channels (Kv) and the rapidly activating K+ channel (KA ) share a similar putative hexaspanning structure similar in overall configuration to one repeat unit within the Na+ and Ca2+ channel structure, while the inwardly rectifying K+ channel protein (Kir) retains the general configuration of just loops five and six. Regulatory β subunits (cystosolic) can alter Kv channel functions. Channels of these two overall motifs can form heteromultimers.
Figure 14-3. Structure models of three families of Cl− channel. A. The γ-aminobutyric acid (GABA) and glycine receptor channels. B. CLC Cl− channel. C. CFTR (cystic fibrosis transmembrane condiuctance regulator) channel. (M, transmembrane domains; NBF, nucleotide-binding fold; R, regulatory [phosphorylation] domain.) (Reproduced with permission from Jentsch J. Chloride channels: A molecular perspective. Curr Opin Neurobiol, 1996, 6:303–310. Copyright © Elsevier.)
Figure 14-4. Predicted 3-D structure of a ligand-gated ion channel receptor in a postsynaptic membrane. A. These channels consist of a cylindrical membrane-embedded structure with a central pore. The second transmembrane domain (TM2) of each subunit lines the pore and bends inward to block ion flow through the channel. B. A highly conserved leucine residue (L) in the TM2 bend of each subunit is believed to protrude into the pore to form a tight hydrophobic ring, which may act as a barrier to the flow of hydrated ions across the channel. (Redrawn with permission from Nestler EJ, Hyman SE, Malenka RC (eds). Molecular Neuropharmacology. New York: McGraw-Hill, 2000, p 174. Copyright © 2009 by The McGraw-Hill Companies, Inc. All rights reserved.)
Table 14-1 Subtypes of Ca2+ Cannela
Figure 14-5. General Patterns of Signal Transduction in the Brain. A. Neurotransmitter activation of a receptor that contains an integral ion channel. B. Neurotransmitter activation of G protein-coupled receptor. After activation, the βγ subunits of the G protein can directly regulate an ion channel (left), and the α subunit can activate second messenger-dependent signaling involving protein kinases and protein phosphatases, which can, in turn, affect ion channels and other neuronal processes (right). C. Neurotrophic factors promote receptor dimerization, which leads to activation of receptor protein tyrosine kinase activity and its sequelae. D. Steroid hormone activation of a cytoplasmic receptor. After the receptor-hormone complex forms, it enters the nucleus and regulates gene expression (see Figure 6-12). (Redrawn with permission from Nestler EJ, Hyman SE, Malenka RC (eds). Molecular Neuropharmacology. New York: McGraw-Hill, 2000, p 76. Copyright © 2009 by The McGraw-Hill Companies, Inc. All rights reserved.)
NEUROTRANSMITTER RECEPTOR-EFFECTOR COUPLING IN THE CNS
Figure 14-6. The β adrenergic receptor (βAR). This two-dimensional bead-on-a string model illustrates features common to most heptaspanning GPCRs. Red lines mark 10-amino acid regions. The amino terminus (N) is extracellular and the carboxyl terminus (C) is intracellular; in between are 7 hydrophobic transmembrane (TM) domains and alternating intracellular and extracellular loops (e1–3 and i1–3). Glycosylation sites are found near the N terminus; consensus sites for phophorylation by PKA (arrows) are found in the i3 loop and the carboxy terminal tail. Multiple sites for βARK occur throughout the carboxy terminal region. An aspartate residue in TM3 (asp113) interacts with the nitrogen of catecholamine agonists while two serines (ser204, ser207) in TM5 interact with the hydroxyl groups on the phenyl ring of catecholamine agonists. A cysteine residue (cys 341) is a substrate for palmitoylation. Interaction of the palmitoyl group with membrane lipids reduces the flexibility of the carboxy tail. (Reprinted by permission from Macmillan Publishers Ltd: Rasmussen SGF, Choi H-J, Rosenbaum DM et al: Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450:383, 2007. Copyright © 2007.)
CELL SIGNALING AND SYNAPTIC TRANSMISSION
Figure 14-7. Transmitter release, action, and inactivation. Depolarization opens voltage-dependent Ca2+ channels in the presynaptic nerve terminal. (1) The influx of Ca2+ during an action potential (AP) triggers (2) the exocytosis of small synaptic vesicles that store neurotransmitter (NT) involved in fast neurotransmission. Released neurotransmitter interacts with receptors in the postsynaptic membranes that either couple directly with ion channels (3) or act through second messengers, such as (4) GPCRs. Neurotransmitter receptors in the presynaptic nerve terminal membrane (5) can inhibit or enhance subsequent exocytosis. Released neurotransmitter is inactivated by reuptake into the nerve terminal by (6) a transport protein coupled to the Na+ gradient, for example, DA, NE, and GABA; by (7) degradation (ACh, peptides); or by (8) uptake and metabolism by glial cells (Glu). The synaptic vesicle membrane is recycled by (9) clathrin-mediated endocytosis. Neuropeptides and proteins are stored in (10) larger, dense core granules within the nerve terminal. These dense core granules are released from (11) sites distinct from active zones after repetitive stimulation.
Figure 14-8. Structure of the rat 5-HT transport protein. Both the N terminus (NH3+) and C terminus (COO−) are intracellular. These proteins typically have 12 hydrophobic, membrane-spanning domains with intervening extracellular and intracellular loops. The second extracellular loop is the largest and contains several potential glycosylation sites (indicated with tree-like symbols). Amino acid residues which are homologous to those in the DA transporter (DAT) and the NE transporter (NET) are colored, as noted. The most highly conserved regions of these transporters are located in the transmembrane domains; the most divergent areas occur in the N and C termini. (Courtesy of Dr. Beth J. Hoffman, Vertex Pharmaceuticals, San Diego.)
Figure 14-9. Relationship between the hypothalamus and the pituitary gland. The anterior pituitary, or adenohypophysis, receives a rich blood flow from the capillaries of the portal hypophyseal system. This system delivers factors released by hypothalamic neurons into portal capillaries at the median eminence. The figure shows one such projection, from the tuberal (arcuate) nuclei via the tuberoinfundibular tract to the median eminence. The posterior pituitary, or neurohypophysis, contains axon terminals of neurons projecting from the paraventricular and supraoptic nuclei of the hypothalamus. For endocrinological detail, see Figure 38-1.
CENTRAL NEUROTRANSMITTERS
Figure 14-10. Amino acid transmitters and congeners.
Figure 14-11. Pharmacologic binding sites on the GABAA receptor. (Reproduced with permission from Nestler EJ, Hyman SE, Malenka RC (eds). Molecular Neuropharmacology. New York: McGraw-Hill, 2000, p 135. Copyright © 2009 by The McGraw- Hill Companies, Inc. All rights reserved.)
Table 14-2 Composition, Distribution, and Major Functions of GABAA Receptors
Table 14-3 Classification of Glutamate and Aspartate Receptorsa
Figure 14-12. Major forms of NMDA receptor-dependent LTP and LTD. A. NMDA receptor-dependent LTP requires post synaptic NMDA receptor activation leading to a rise in Ca2+ and activation of CaM kinase II (CaMKII). AMPA receptor insertion into the postsynaptic membrane is a major mechanism underlying LTP expression. B. NMDA receptor-dependent LTD is triggered by Ca2+ entry through post synaptic NMDA receptor channels, leading to increases in the activity of the protein phosphatases calcineurin and PP1. LTD occurs when postsynaptic AMPA receptors are internalized. (Redrawn with permission from Nestler EJ, Hyman SE, Malenka RC (eds). Molecular Neuropharmacology. New York: McGraw-Hill, 2000, p 132. Copyright © 2009 by The McGraw-Hill Companies, Inc. All rights reserved.)
Figure 14-13. Mechanisms contributing to neuronal injury during ischemia-reperfusion. Several pathways contribute to excitotoxic neuronal injury in ischemia, with excess cytosolic Ca2+ playing a precipitating role. DAG, diacylglycerol; GluR, AMPA/kainate type of glutamate receptors; IP3, inositol trisphosphate; mGluR, metabotropic glutamate receptor; NMDA-R, N—methyl-D-aspartate receptor; O2−, superoxide radical; PIP2, phophatidyinositol 4,5-bisphosphate; PKC, protein kinase C; PL, phospholipids, PL phospholipase, VSCC, voltage-sensitive Ca2+ channel. COX, cyclooxygenase; LOX, lipoxygenase; NCX, NA+/Ca2+ exchanger; mtPTP, mitochondrial permeability transition pore. (Reproduced with permission from Dugan LL, Kim-Han JS: Hypoxic-ischemic brain injury and oxidative stress, in Siegel GS, Albers RW, Brady S, Price D (eds): Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 7th ed. Burlington, MA: Elsevier Academic Press, 2006, p 564. Copyright © 2006, American Society for Neurochemistry. All rights reserved.)
Table 14-4 Subtypes of Muscarinic Receptors in the CNS
Figure 14-14. The three major dopaminergic projections in the CNS. 1. The mesostriatal (or nigrostriatal) pathway. Neurons in the substantia nigra pars compacta (SNc) project to the dorsal striatum (upward dashed blue arrows); this is the pathway that degenerates in Parkinson disease. 2. Neurons in the ventral tegmental area project to the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cinguate gyrus (solid blue arrows). 3. Neurons in the arcuate nucleus of the hypothalamus project by the tuberoinfundibular pathway in the hypothalamus, from which DA is delivered to the anterior pituitary (red arrows).
Table 14-5 Dopamine Receptors in the CNS
Table 14-6 Adrenergic Receptors in the CNS
Table 14-7 5-HT Receptors in the CNS
Figure 14-15. Main signaling pathways for histamine receptors. Histamine can couple to a variety of G protein-linked signal transduction pathways via four different receptors. The H1 receptor and some H4 receptors activate phosphatidylinositol turnover via Gq/11. The other receptors couple either positively (H2 receptor) or negatively (H3 and H4 receptor) to adenylyl cyclase activity via Gs and Gi/o.
Table 14-8 Examples of Neuropeptides
Figure 14-16. Proteolytic processing of praopiomelanocortin (POMC). After removal of the signal peptide from pre-POMC, the remaining propeptide undergoes endoprotolysis by prohormone convertases 1 and 2 (PC1 and PC2) at dibasic residues. PC1 liberates the bioactive peptides adrenocorticotropic hormone (ACTH), β-endorphin (β end), and γ-lipotrophic hormone (γ-LPH). PC2 cleaves ACTH into corticotrophin-like intermediate lobe peptide (CLIP) and α-melanocyte stimulating hormone (α-MSH) and also releases γ-MSH from the N-terminal portion of the propeptide. The joining peptide (JP) is the region between ACTH and γ-MSH. β-MSH is formed by cleavage of γ-LPH. Some of the resulting peptides are amidated or acetylated before they become fully active.
Other Regulatory Substances
Table 14-9 Peptide transmitters and receptors
Figure 14-17. Cannabinoid receptor ligands. Anandamide and 2-arachidonylglycerol are endogenous agonists. Rimonabant is a synthetic CB receptor antagonist. Δ9-tetrahydrocannabinol is a CB agonist derived from marijuana.
ACTIONS OF DRUGS IN THE CNS
Specificity and Nonspecificity of CNS Drug Actions
General (Nonspecific) CNS Depressants
Table 14-10 Characteristics of Purinergic Receptors
General (Nonspecific) CNS Stimulants
Drugs That Selectively Modify CNS Function
General Characteristics of CNS Drugs
BIBLIOGRAPHY
chapter 15 Drug Therapy of Depression and Anxiety Disorders
CHARACTERIZATION OF DEPRESSIVE AND ANXIETY DISORDER
Symptoms of Depression
Symptoms of Anxiety
ANTIDEPRESSANT DRUGS
Figure 15-1. Sites of action of antidepressants. Schematics representing noradrenergic (top) and serotonergic (bottom) nerve terminals. SSRIs, SNRIs, and TCAs increase noradrenergic or serotonergic neurotransmission by blocking the norepinephrine or serotonergic transporter at presynaptic terminals (NET, SERT). MAOIs inhibit the catabolism of norepinephrine and serotonin. Some antidepressants such as trazodone and related drugs have direct effects on serotonergic receptors that contribute to their clinical effects. Chronic treatment with a number of antidepressants desensitizes presynaptic autoreceptors and heteroreceptors, producing long-lasting changes in monoaminergic neurotransmission. Post-receptor effects of antidepressant treatment, including modulation of GPCR signaling and activation of protein kinases and ion channels, are involved in the mediation of the long-term effects of antidepressant drugs. Note that NE and 5-HT also affect each other's neurons.
Clinical Considerations with Antidepressant Drugs
Table 15-1 Antidepressants: Chemical Structures, Dose and Dosage Forms, and Side Effects
Monoamine Oxidase Inhibitors
Tricyclic Antidepressant and Selective Reuptake Inhibitors
Selective Serotonin Reuptake Inhibitors
Serotonin-Norepinephrine Reuptake Inhibitors
Table 15-2 Potencies of Antidepressants at the Human Transporters for Norepinephrine (NET), Serotonin (SERT), and Dopamine (DAT)
Serotonin Receptor Antagonists
Bupropion
Atypical Antipsychotics
Tricyclic Antidepressants
Monoamine Oxidase Inhibitors
Pharmacokinetics
Table 15-3 Disposition of Antidepressants
Adverse Effects
Table 15-4 Potencies of Selected Antidepressants at Muscarinic, Histamine H1, and Alpha1 Adrenergic Receptors
Drug Interactions
Anxiolytic Drugs
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 16 Pharmacotherapy of Psychosis and Mania
TREATMENT OF PSYCHOSIS
Review of Relevant Pathophysiology
Review of Psychosis Pathology and the General Goals of Pharmacotherapy
Short-Term Treatment
Figure 16-1. Sites of action of antipsychotic agents and Li+. In varicosities ("terminals") along terminal arborizations of dopaminergic neurons projecting from midbrain to forebrain, DA is synthesized and stored in vesicles. Following exocytotic release, DA interacts with postsynaptic receptors (R) of D1 and D2 types, and presynaptic D2 and D3 autoreceptors. Termination of DA action occurs primarily by active transport of DA into presynaptic terminals via the DA transporter DAT, with secondary deamination by mitochondrial monoamine oxidase (MAO). Stimulation of postsynaptic D1 receptors activates the Gs-adenylyl cyclase-cAMP pathway. D2 receptors couple through Gi to inhibit adenylyl cyclase and through Gq to activate the PLC-IP3-Ca2+ pathway. Activation of the Gi pathway can also activate K+ channels, leading to hyperpolarization. Lithium inhibits the phosphatase that liberates inositol (I) from inositol phosphate (IP). Li+ can also inhibit depolarization-evoked release of DA and NE, but not 5-HT. D2-like autoreceptors suppress synthesis of DA by diminishing phosphorylation of rate-limiting TH, and by limiting DA release. In contrast, presynaptic A2 adenosine receptors (A2R) activate AC and, through cyclic AMP production, TH activity. All antipsychotic agents act at D2 receptors and autoreceptors; some also block D1 receptors (Table 16-2). Stimulant agents inhibit DA re-uptake by DAT, thereby prolonging the dwell time of synaptic DA. Initially in antipsychotic treatment, DA neurons release more DA, but following repeated treatment, they enter a state of physiological depolarization inactivation, with diminished production and release of DA, in addition to continued receptor blockade. , inhibition or blockade; +, elevation of activity; −, reduction of activity.
Figure 16-2. Receptor occupancy and clinical response for antipsychotic agents. Typically, in D2 receptor occupancy by the drug >60% provides antipsychotic effects, receptor occupancy >80% causes extrapyramidal symptoms (EPS). Atypical agents combine weak D2 receptor blockade with more potent 5-HT2A antagonism/inverse agonism. Inverse agonism at 5-HT2 receptor subtypes may contribute to the reduced EPS risk of olanzapine (Panel A) and risperidone (Panel B) and efficacy at lower D2 receptor occupancy (olanzapine, Panel A). Aripiprazole is a partial D2 agonist that can achieve only 75% functional blockade (Figure 16-3).
Long-Term Treatment
Table 16-1 Chemical Structures, Dosages for Acute Psychosis and Schizophrenia Maintenance, and Metabolic Risk Profilea
Table 16-2 Potencies of Antipsychotic Agents at Neurotransmitter Receptorsa
Pharmacology of Antipsychotic Agents
Figure 16-3. Aripiprazole activity at D2 receptors in the presence or absence of dopamine. Aripiprazole is a partial D2 agonist; thus it inhibits effects of DA and reduces stimulation at the D2 receptor only to the extent of its own capacity as an agonist. Haloperidol, an antagonist without agonist activity, completely antagonizes D2 receptor activation. Here, receptor activity was measured as inhibition of forskolin-induced cAMP accumulation in CHO cells transfected with human D2L DNA. Adapted from (Burris et al., 2002.)
Table 16-3 Metabolism of Common Antipsychotic Drugs
Therapeutic Uses
Adverse Effects and Drug Interactions
Adverse Effects Predicted by Monoamine Receptor Affinities
Table 16-4 Neurological Side Effects of Antipsychotic Drugs
Adverse Effects Not Predicted by Monoamine Receptor Affinities
Major Drugs Available in the Class
Clinical Summary: Treatment of Psychosis
TREATMENT OF MANIA
Pharmacological Properties of Agents for Mania
Therapeutic Uses
Adverse Effects
Use in Pediatric and Geriatric Populations
Major Drugs Available in the Class
Novel Treatments for Psychosis and Mania
Clinical Summary: Treatment of Mania
BIBLIOGRAPHY
chapter 17 Hypnotics and Sedatives
BENZODIAZEPINES
Pharmacological Properties
Table 17-1 Benzodiazepines: Names and Structures*
Table 17-2 Major Meabolic Relationships among Some of Benzodiazepinesa
Therapeutic Uses
Table 17-3 Trade Names, Routes of Administration, and Therapeutic Uses of Benzodiazepines
Novel Benzodiazepine Receptor Agonists
FLUMAZENIL: A BENZODIAZEPINE RECEPTOR ANTAGONIST
MELATONIN CONGENERS
BARBITURATES
Table 17-4 Structures, Trade Names, and Major Pharmacological Properties of Selected Barbiturates
Pharmacological Properties
Central Nervous System
Therapeutic Uses
Untoward Effects
MISCELLANEOUS SEDATIVE-HYPNOTIC DRUGS
MANAGEMENT OF INSOMNIA
BIBLIOGRAPHY
chapter 18 Opioids, Analgesia, and Pain Management
ENDOGENOUS OPIOID SYSTEMS: AGONISTS AND RECEPTORS
OPIOID RECEPTORS
Principal Receptor Classes; Distribution
Table 18-1 Actions and Selectivities of Some Opioids at µ, δ, and κ Receptors
Opiate Receptor Subtypes
Alternative Splicing of Receptor RNA
Receptor Subtype Agonists/Antagonists
Receptor Structure
Figure 18-2. Human pro-orphanin-derived peptides.
Structural Correlates of Binding/Coupling Requirements for Opiate Ligands
Opiate Receptor Coupling to Membrane Function
Regulation of Opiate Receptor Disposition
Functional Consequences of Acute and Chronic Opiate Receptor Activation
Figure 18-3. Structural features of opioid ligands contribute to receptor selectivity. The "message-linker-address" formulation (Takemore and Portoghese, 1992) has been refined and used to synthesize non-peptide ligands that exhibit predicted opiate receptor specificity. The ligands pictured above demonstrate some of the common (message) and variable (linker and address) features thought to contribute to ligand-receptor interactions for both opiate receptor agonists and antagonists.
Mechanisms of Tolerance/Dependence-Withdrawal
Effect Profile of Clinically Used Opioids
Figure 18-4. Mechanistic flow diagram of tissue injury-evoked nociception.
Figure 18-5. Mechanistic flow diagram of nerve injury-evoked nociception.
Figure 18-6. Mechanisms of opiate action in producing analgesia. Top left: Schematic of organization of opiate action in the periaqueductal gray. Top right: Opiate-sensitive pathways in PAG Mu opiate actions block the release of GABA from tonically active systems that otherwise regulate the projections to the medulla (1) leading to an activation of PAG outflow resulting and activation of forebrain (2) and spinal (3) monoamine receptors that regulate spinal cord projections (4) which provide sensory input to higher centers and mood. Bottom left: Schematic of primary afferent synapse with second order dorsal horn spinal neuron, showing pre- and post-synaptic opiate receptors coupled to Ca2+ and K+ channels, respectively. Opiate receptor binding is highly expressed in the superficial spinal dorsal horn (substantia gelatinosa). These receptors are located presynaptically on the terminals of small primary afferents (C fibers) and postsynaptially on second order neurons. Presynaptically, activation of MOR blocks the opening of the voltage sensitve Ca2+ channel, which otherwise initiates transmitter release. Postsynaptically, MOR activation enhances opening of K+ channels, leading to hyperpolarization. Thus, an opiate agonist acting at these sites jointly serves to attenuate the afferent-evoked excitation of the second order neuron.
Figure 18-7. Schematic pathways underlying rewarding properties of opiates. Upper panel: This saggital section of rat brain displays simplified DA and GABA inputs from the ventral tegmental area (VTA) and prefrontal cortex (PFC), respectively, into the nucleus accumbens (NAc). Lower panel: Neurons are labeled with their primary neurotransmitters. At a cellular level, MOR agonists reduce excitability and transmitter release at the sites indicated by inhbiting Ca2+ influx and enhancing K+ current (see Figure 18-6). Thus, opiateinduced inhibition in theVTA on GABA-ergic interneurons or in the NAc reduce GABA-mediated inhibition and increase outflow from the ventral pallidum (VP), which appears to correlate with a positive reinforcing state (enhanced reward).
Other Smooth Muscle
FUNCTIONAL OPIOID DRUG TYPES
MORPHINE AND STRUCTURALLY RELATED AGONISTS
Source and Composition of Opium
Table 18-2 Dosing Data for Clinically Employed Opioid Analgesics
Chemistry of Morphine and Its Congeners
Structure-Activity Relationship of the Morphine-Like Opioids.
Absorption, Distribution, Metabolism, and Excretion
Figure 18-8. Structures of morphine-related opiate agonists and antagonists.
Therapeutic Actions and Precautions
LEVORPHANOL
MEPERIDINE, DIPHENOXYLATE, LOPERAMIDE
Meperidine
Effects on Organ Systems
Absorption, Distribution, Metabolism, and Excretion.
Figure 18-9. Chemical structures of piperidine and phenylpiperidine analgesics.
Diphenoxylate
Loperamide
FENTANYL AND CONGENERS
Fentanyl
Pharmacological Properties
Remifentanil
METHADONE AND PROPOXYPHENE
Methadone
Propoxyphene
Other Opioid Agonists
OPIOID AGONISTS/ANTAGONISTS AND PARTIAL AGONISTS
Pentazocine
Nalbuphine
Butorphanol
Buprenorphine
OPIOID ANTAGONISTS
Pharmacological Properties
Effects in the Presence of Opioid Agonists
Absorption, Distribution, Metabolism, and Excretion
Therapeutic Uses
CENTRALLY ACTIVE ANTITUSSIVES
Dextromethorphan
Other Antitussives
ROUTES OF ANALGESIC DRUG ADMINISTRATION
Patient-Controlled Analgesia (PCA)
Spinal Delivery
Table 18-3 Epidural or Intrathecal Opioids for the Treatment of Acute (Bolus) or Chronic (Infusion) Pain
Local Drug Action
Rectal Administration
Inhalation
Oral Transmucosal Administration
Transnasal Administration
Transdermal and Iontophoretic Administration
THERAPEUTIC USE OF OPIATES IN PAIN CONTROL
Table 18-4 Resources for Pain Management
Guidelines for Opiate Dosing
Table 18-5 World Health Organization Analgesic Laddera
Variables Modifying the Therapeutic Response to Opiates
Table 18-6 Guidelines for the Use of Opioids to Treat Chronic Pain
Table 18-7 Oral Morphine to Methadone Conversion Guidelines
NON-ANALGESIC THERAPEUTIC USES OF OPIOIDS
Dyspnea
Anesthetic Adjuvants
TREATMENT OF ACUTE OPIOID TOXICITY
Table 18-8 Summary of Drug Target and Site of Action of Common Drug Classes and Relative Efficacy by Pain State
Symptoms and Diagnosis
Treatment
CLINICAL SUMMARY
Pain of Terminal Illness and Cancer Pain
BIBLIOGRAPHY
chapter 19 General Anesthetics and Therapeutic Gases
General Anesthetics
GENERAL PRINCIPLES OF SURGICAL ANESTHESIA
ACTIONS AND MECHANISMS OF GENERAL ANESTHETICS
The Anesthetic State
Measurement of Anesthetic Potency
Table 19-1 Properties of Inhalational Anesthetic Agents
Mechanisms of Anesthesia
PARENTERAL ANESTHETICS
Pharmacokinetic Principles
Figure 19-1. Structures of some parenteral anesthetics.
Figure 19-2. Thiopental serum levels after a single intravenous induction dose. Thiopental serum levels after a bolus can be described by two time constants, t1/2α and t1/2β. The initial fall is rapid (t1/2α <10 min) and is due to redistribution of drug from the plasma and the highly perfused brain and spinal cord into less well-perfused tissues such as muscle and fat. During this redistribution phase, serum thiopental concentration falls to levels at which patients awaken (AL, awakening level; see inset—the average thiopental serum concentration in 12 patients after a 6-mg/kg intravenous bolus of thiopental). Subsequent metabolism and elimination is much slower and is characterized by a half-life (t1/2 β) of more than 10 hours. (Adapted with permission from Burch PG, and Stanski DR, The role of metabolism and protein binding in thiopental anesthesia. Anesthesiology, 1983, 58:146–152. Copyright Lippincott Williams & Wilkins. http://lww.com.)
SPECIFIC PARENTERAL AGENTS
Barbiturates
Table 19-2 Pharmacological Properties of Parenteral Anesthetics
Figure 19-3. Context-sensitive half-time of general anesthetics. The duration of action of single intravenous doses of anesthetic/hypnotic drugs is similarly short for all and is determined by redistribution of the drugs away from their active sites (see Figure 19-2). However, after prolonged infusions, drug half-lives and durations of action are dependent on a complex interaction between the rate of redistribution of the drug, the amount of drug accumulated in fat, and the drug's metabolic rate. This phenomenon has been termed the context-sensitive half-time; that is, the t1/2 of a drug can be estimated only if one knows the context—the total dose and over what time period it has been given. Note that the half-times of some drugs such as etomidate, propofol, and ketamine increase only modestly with prolonged infusions; others (e.g., diazepam and thiopental) increase dramatically. (Reproduced with permission from Reves JG, Glass PSA, Lubarsky DA, et al: Intravenous anesthetics, in Miller RD et al, (eds): Miller's Anesthesia, 7th ed. Philadelphia: Churchill Livingstone, 2010, p 718. Copyright © Elsevier.)
Side Effects
Propofol
Pharmacology and Side Effects
Etomidate
Side Effects
Ketamine
Side Effects
Summary of Parenteral Anesthetics
INHALATIONAL ANESTHETICS
Introduction
Table 19-3 Some Pharmacological Effects of Parenteral Anestheticsa
Pharmacokinetic Principles
Figure 19-4. Structures of inhalational general anesthetics. Note that all inhalational general anesthetic agents except nitrous oxide and halothane are ethers, and that fluorine progressively replaces other halogens in the development of the halogenated agents. All structural differences are associated with important differences in pharmacological properties.
Figure 19-5. Uptake of inhalational general anesthetics. The rise in end-tidal alveolar (FA) anesthetic concentration toward the inspired (FI) concentration is most rapid with the least soluble anesthetics, nitrous oxide and desflurane, and slowest with the most soluble anesthetic, halothane. All data are from human studies. (Reproduced with permission from Eger EI, II: Inhaled anesthetics: Uptake and distribution, in Miller RD et al, (eds): Miller's Anesthesia, 7th ed. Philadelphia: Churchill Livingstone, 2010, p 540. Copyright © Elsevier.)
Halothane
Side Effects
Figure 19-6. Influence of inhalational general anesthetics on the systemic circulation. While all of the inhalational anesthetics reduce systemic blood pressure in a dose-related manner (top), the lower figure shows that cardiac output is well preserved with isoflurane and desflurane, and therefore that the causes of hypotension vary with the agent. (Data from Bahlman et al., 1972; Calverley et al., 1978; Cromwell et al., 1971; Stevens et al., 1971; Weiskopf et al., 1991).
Figure 19-7. Respiratory effects of inhalational anesthetics. Spontaneous ventilation with all of the halogenated inhalational anesthetics reduces minute volume of ventilation in a dose-dependent manner (lower panel). This results in an increased arterial carbon dioxide tension (top panel). Differences among agents are modest. (Data from Calverley et al., 1978; Doi and Ikeda, 1987; Fourcade et al., 1971; Lockhart et al., 1991; Munson et al., 1966.)
Isoflurane
Side Effects
Enflurane
Side Effects
Desflurane
Side Effects
Sevoflurane
Side Effects
Nitrous Oxide
Side Effects
Xenon
Effects on Organ Systems
ANESTHETIC ADJUNCTS
Benzodiazepines
Analgesics
Neuromuscular Blocking Agents
ANESTHETIC CYTOPROTECTION AND TOXICITY
Therapeutic Gases
OXYGEN
Normal Oxygenation
Figure 19-8. Oxyhemoglobin dissociation curve for whole blood. The relationship between Po2 and hemoglobin (Hb) saturation is shown. The P50, or the Po2 resulting in 50% saturation, is indicated as well. An increase in temperature or a decrease in pH (as in working muscle) shifts this relationship to the right, reducing the hemoglobin saturation at the same Po2 and thus aiding in the delivery of oxygen to the tissues.
Oxygen Deprivation
Table 19-4 The Carriage of Oxygen in Blooda
Figure 19-9. Effect of shunt on arterial oxygenation. The isoshunt diagram shows the effect of changing inspired oxygen concentration on arterial oxygenation in the presence of different amounts of pure shunt. As shunt fraction increases, even an inspired oxygen fraction (FiO2 ) of 1.0 is ineffective at increasing the arterial Po2. This estimation assumes hemoglobin (Hb) 10–14 g/dL, arterial PCO2 3.3–5.3 kPa (25–40 mm Hg), and an arterial-venous (a-v) O2 content difference of 5 mL/100 mL. (Redrawn from Benatar SR, Hewlett AM, Nunn JF. The use of iso-shunt lines for control of oxygen therapy. Br J Anaesth, 1973, 45:711–718, with permission. Copyright © The Board of Management and Trustees of the British Journal of Anaesthesia. Reproduced with permission of Oxford University Press/British Journal of Anaesthesia.)
Oxygen Inhalation
Oxygen Administration
Therapeutic Uses of Oxygen
Oxygen Toxicity
CARBON DIOXIDE
Transfer and Elimination of CO2
Effects of Carbon Dioxide
NITRIC OXIDE
HELIUM
HYDROGEN SULFIDE
BIBLIOGRAPHY
chapter 20 Local Anesthetics
Figure 20-1. Structural formulas of selected local anesthetics. Most local anesthetics consist of a hydrophobic (aromatic) moiety (black), a linker region (orange), and a substituted amine (hydrophilic region, in red). The structures above are grouped by the nature of the linker region. Procaine is a prototypic ester-type local anesthetic; esters generally are well hydrolyzed by plasma esterases, contributing to the relatively short duration of action of drugs in this group. Lidocaine is a prototypic amide-type local anesthetic; these structures generally are more resistant to clearance and have longer durations of action. There are exceptions, including benzocaine (poorly water soluble; used only topically) and the structures with a ketone, an amidine, and an ether linkage. Chloroprocaine has a chlorine atom on C2 of the aromatic ring of procaine.
Figure 20-2. Structure and function of voltage-gated Na+ channels. A. A two-dimensional representation of the α (center), β1(left), and β2(right) subunits of the voltage-gated Na+ channel from mammalian brain. The polypeptide chains are represented by continuous lines with length approximately proportional to the actual length of each segment of the channel protein. Cylinders represent regions of transmembrane α helices. ψ indicates sites of demonstrated N-linked glycosylation. Note the repeated structure of the four homologous domains (I–IV) of the α subunit. Voltage Sensing. The S4 transmembrane segments in each homologous domain of the α subunit serve as voltage sensors. (+) represents the positively charged amino acid residues at every third position within these segments. Electrical field (negative inside) exerts a force on these charged amino acid residues, pulling them toward the intracellular side of the membrane; depolarization allows them to move outward. Pore. The S5 and S6 transmembrane segments and the short membrane-associated loop between them (P loop) form the walls of the pore in the center of an approximately symmetrical square array of the four homologous domains (see panel B). The amino acid residues indicated by circles in the P loop are critical for determining the conductance and ion selectivity of the Na+ channel and its ability to bind the extracellular pore-blocking toxins tetrodotoxin and saxitoxin. Inactivation. The short intracellular loop connecting homologous domains III and IV serves as the inactivation gate of the Na+ channel. It is thought to fold into the intracellular mouth of the pore and occlude it within a few milliseconds after the channel opens. Three hydrophobic residues (isoleucine-phenylalanine-methionine; IFM) at the position marked h appear to serve as an inactivation particle, entering the intracellular mouth of the pore and binding therein to an inactivation gate receptor there. Modulation. The gating of the Na+ channel can be modulated by protein phosphorylation. Phosphorylation of the inactivation gate between homologous domains III and IV by PKC slows inactivation. Phosphorylation of sites in the intracellular loop between homologous domains I and II by either PKC or PKA reduces Na+ channel activation. (Adapted from Catterall, 2000, with permission.Copyright © Elsevier.). B. The four homologous domains of the Na+ channel α subunit are illustrated as a square array, as viewed looking down on the membrane. The sequence of conformational changes that the Na+ channel undergoes during activation and inactivation is diagrammed. Upon depolarization, each of the four homologous domains sequentially undergoes a conformational change to an activated state. After all four domains have activated, the Na+ channel can open. Within a few milliseconds after opening, the inactivation gate between domains III and IV closes over the intracellular mouth of the channel and occludes it, preventing further ion conductance (see Catterall, 2000).
Figure 20-3. The local anesthetic receptor site. A. A drawing of the pore structure of a bacterial K+ channel (KcsA), which is related to the sodium channel. The KcsA channel has two transmembrane segments, analogous to the S5 and S6 segments of sodium channels. The S6-like segment forms the walls of the inner pore while the P loop forms the narrow ion selectivity filter at its extracellular (top) end. Four separate KcsA subunits form the pore in their center; only two of the subunits are shown here. B. A structural model of the local anesthetic receptor site. The S6 segments from domains I, III, and IV of the sodium channel α subunit are illustrated, based on the structure of the KcsA channel (panel A). The amino acid residues in these three transmembrane segments that contribute to the local anesthetic receptor site are indicated in single letter code and are presented in space-filling representation (light blue). An etidocaine molecule (black) is illustrated bound in the receptor site. Substitutions of the light blue residues with alanine reduce the affinity for local anesthetic block of sodium channels. It therefore is likely that the side chains of these amino acid residues contact bound local anesthetics in their receptor site. I1760 and I409 likely form the outer boundary of the local anesthetic receptor site. Mutations of I1760 allow drug access to the receptor site from the extracellular side. (This figure was originally published in the Journal of Biological Chemistry. Yarov-Yarovoy V, McPhee JC, Idsvoog D, Pate C, Scheuer T, Catterall WA: Role of amino acid resides in transmembrane segments IS6 and IIS6 of the Na+ channel alpha subunit in voltage-dependent gating and drug block. J Biol Chem 2002:277, 35393. © the American Society for Biochemistry and Molecular Biology.)
Table 20-1 Susceptibility to Block Types of Nerve Fibers
COCAINE
LIDOCAINE
BUPIVACAINE
OTHER SYNTHETIC LOCAL ANESTHETICS
Local Anesthetics Suitable for Injection
Local Anesthetics Used Primarily to Anesthetize Mucous Membranes and Skin
Anesthetics of Low Solubility
Local Anesthetics Largely Restricted to Ophthalmological Use
BIOLOGICAL TOXINS: TETRODOTOXIN AND SAXITOXIN
CLINICAL USES OF LOCAL ANESTHETICS
Topical Anesthesia
Infiltration Anesthesia
Field Block Anesthesia
Nerve Block Anesthesia
Intravenous Regional Anesthesia (Bier's Block)
Spinal Anesthesia
Epidural Anesthesia
BIBLIOGRAPHY
chapter 21 Pharmacotherapy of the Epilepsies
TERMINOLOGY AND EPILEPTIC SEIZURE CLASSIFICATION
Table 21-1 Classification of Epileptic Seizures
NATURE AND MECHANISMS OF SEIZURES AND ANTI-SEIZURE DRUGS
Partial Epilepsies
Figure 21-1. Relations among cortical EEG, extracellular, and intracellular recordings in a seizure focus induced by local application of a convulsant agent to mammalian cortex. The extracellular recording was made through a high-pass filter. Note the high-frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal depolarization shift (PDS). (Modified with permission from Ayala GF, Dichter M, Gumnit RJ, et al. Genesis of epileptic interictal spikes. New knowledge of cortical feedback systems suggests a neurophysiological explanation of brief paroxysms. Brain Res, 1973, 52:1–17. Copyright © Elsevier.)
Table 21-2 Proposed Mechanisms of Action of Anti-Seizure Drugs
Figure 21-2. Anti-seizure drug-enhanced Na+ channel inactivation. Some anti-seizure drugs (shown in blue text) prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies. Note that the inactivated channel itself appears to remain open, but is blocked by the inactivation gate I. A, activation gate.
Figure 21-3. Enhanced GABA synaptic transmission. In the presence of GABA, the GABAA receptor (structure on left) is opened, allowing an influx of Cl-, which in turn increases membrane polarization (Chapter 14). Some anti-seizure drugs (show in larger blue text) act by reducing the metabolism of GABA. Others act at the GABAA receptor, enhancing Cl- influx in response to GABA. As outlined in the text, gabapentin acts presynaptically to promote GABA release; its molecular target is currently under investigation. GABA molecules, GABA-T, GABA transaminase; GAT-1, GABA transporter.
Generalized-Onset Epilepsies: Absence Seizures
Genetic Approaches to the Epilepsies
Figure 21-4. Anti-seizure drug-induced reduction of current through T-type Ca2+ channels. Some anti-seizure drugs (shown in blue text) reduce the flow of Ca2+ through T-type Ca2+ channels thus reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures.
ANTI-SEIZURE DRUGS: GENERAL CONSIDERATIONS
HYDANTOINS
Phenytoin
Pharmacological Effects
Table 21-3 Interactions of Anti-Seizure Drugs with Hepatic Microsomal Enzymes
Therapeutic Uses
ANTI-SEIZURE BARBITURATES
Phenobarbital
IMINOSTILBENES
Carbamazepine
Oxcarbazepine
SUCCINIMIDES
Ethosuximide
VALPROIC ACID
BENZODIAZEPINES
OTHER ANTI-SEIZURE DRUGS
Gabapentin and Pregabalin
Lamotrigine
Levetiracetam
Tiagabine
Topiramate
Felbamate
Zonisamide
Lacosamide
Rufinamide
Vigabatrin
Acetazolamide
GENERAL PRINCIPLES AND CHOICE OF DRUGS FOR THE THERAPY OF THE EPILEPSIES
Duration of Therapy
Simple and Complex Partial and Secondarily Generalized Tonic-Clonic Seizures
Absence Seizures
Myoclonic Seizures
Febrile Convulsions
Seizures in Infants and Young Children
Status Epilepticus and Other Convulsive Emergencies
Anti-Seizure Therapy and Pregnancy
BIBLIOGRAPHY
chapter 22 Treatment of Central Nervous System Degenerative Disorders
SELECTIVE VULNERABILITY AND NEUROPROTECTIVE STRATEGIES
Parkinson Disease (PD)
Figure 22-1. Dopaminergic nerve terminal. Dopamine (DA) is synthesized from tyrosine in the nerve terminal by the sequential actions of tyrosine hydrolase (TH) and aromatic amino acid decarboxylase (AADC). DA is sequestered by VMAT2 in storage granules and released by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2 receptors. Synaptic DA may be taken up into the neuron via the DA and NE transporters (DAT, NET), or removed by postsynaptic uptake via OCT3 transporters. Cytosolic DA is subject to degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the neuron, and by catechol-O-methyl tranferase (COMT) and MAO/ALDH in non-neuronal cells; the final metabolic product is homovanillic acid (HVA). See structures in Figure 22-4. PH, phenylalanine hydroxylase.
Figure 22-2. Schematic wiring diagram of the basal ganglia. The striatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of cerebral cortex. The striatum contains projection neurons expressing predominantly D1 or D2 dopamine receptors, as well as interneurons that use ACh as a neurotransmitter. Outflow from the striatum proceeds along two routes. The direct pathway, from the striatum to the substantia nigra pars reticulata (SNpr) and globus pallidus interna (GPi), uses the inhibitory transmitter GABA. The indirect pathway, from the striatum through the globus pallidus externa (GPe) and the subthalamic nucleus (STN) to the SNpr and GPi, consists of two inhibitory GABAergic links and one excitatory glutamatergic projection (Glu). The substantia nigra pars compacta (SNpc) provides dopaminergic innervation to the striatal neurons, giving rise to both the direct and indirect pathways, and regulates the relative activity of these two paths. The SNpr and GPi are the output structures of the basal ganglia and provide feedback to the cerebral cortex through the ventroanterior and ventrolateral nuclei of the thalamus (VA/VL).
Figure 22-3. The basal ganglia in Parkinson disease. The primary defect is destruction of the dopaminergic neurons of the SNpc. The striatal neurons that form the direct pathway from the striatum to the SNpr and GPi express primarily the excitatory D1 DA receptor, whereas the striatal neurons that project to the GPe and form the indirect pathway express the inhibitory D2 dopamine receptor. Thus, loss of the dopaminergic input to the striatum has a differential effect on the two outflow pathways; the direct pathway to the SNpr and GPi is less active (structures in purple), whereas the activity in the indirect pathway is increased (structures in red). The net effect is that neurons in the SNpr and GPi become more active. This leads to increased inhibition of the VA/VL thalamus and reduced excitatory input to the cortex. Light blue lines indicate primary pathways with reduced activity. (See legend to Figure 22-2 for definitions of anatomical abbreviations.)
Treatment of Parkinson Disease
Table 22-1 Commonly Used Medications for the Treatment of Parkinson Disease
Figure 22-4. Metabolism of levodopa (l-DOPA). ALDH, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; DβH, dopamine β-hydroxylase; AADC, aromatic L-amino acid decarboxylase; MAO, monoamine oxidase.
Figure 22-5. Pharmacological preservation of l-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-Omethyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AADC, aromatic L-amino acid decarboxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; MAO, monoamine oxidase; 3MT, 3-methoxyltyramine; 3-OMD, 3-O-methyl DOPA
ALZHEIMER'S DISEASE (AD)
Figure 22-6. Molecular and cellular processes presumed to participate in AD pathogenesis. (From Roberson ED, Mucke L. 100 years and counting: Prospects for defeating Alzheimer's disease. Science, 2006, 314:781–784. Reprinted with permission from AAAS.)
Treatment of Alzheimer's Disease
Table 22-2 Cholinesterase Inhibitors Used for the Treatment of Alzheimer's Disease
HUNTINGTON'S DISEASE (HD)
Figure 22-7. The basal ganglia in Huntington's disease. HD is characterized by loss of neurons from the striatum. The neurons that project from the striatum to the GPe and form the indirect pathway are affected earlier in the course of the disease than those which project to the GPi. This leads to a loss of inhibition of the GPe. The increased activity in this structure, in turn, inhibits the STN, SNpr, and GPi, resulting in a loss of inhibition to the VA/VL thalamus and increased thalamocortical excitatory drive. Structures in purple have reduced activity in HD, whereas structures in purple have increased activity. Light blue line indicate primary pathways of reduced activity. (See legend to Figure 22-2 for definitions of anatomical abbreviations.)
Treatment of Huntington's Disease
AMYOTROPHIC LATERAL SCLEROSIS (ALS)
Treatment of ALS
Figure 22-8. Monosynaptic muscle stretch reflex with descending control via inhibitory interneurons. Primary Ia afferents (green) from muscle spindles, activated when the muscle is stretched rapidly, synapse directly on motor neurons (blue) going to the stretched muscle, causing it to contract and resist the movement. Pyramidal upper motor neurons (aqua) from the cerebral cortex suppress spinal reflexes and the lower motor neurons indirectly by activating the spinal cord inhibitory interneuron pools (red). When the pyramidal influences are removed, the reflexes are released from inhibition and become more active, leading to hyperreflexia and spasticity. Baclofen acts to restore the lost inhibition by stimulating postsynaptic GABA receptors. Tizanidine acts presynaptically to stimulate GABA release from spinal cord inhibitory interneuron.
BIBLIOGRAPHY
chapter 23 Ethanol and Methanol
PHARMACOLOGICAL PROPERTIES
Absorption, Distribution, and Metabolism
Figure 23-1. Metabolism of ethanol and methanol.
EFFECTS OF ETHANOL ON PHYSIOLOGICAL SYSTEMS
Central Nervous System
Table 23-1 Impact of Ethanol on Key Neurochemical Systems
Cardiovascular System
Skeletal Muscle
Body Temperature
Diuresis
Gastrointestinal System
Vitamins and Minerals
Sexual Function
Hematological and Immunological Effects
ACUTE ETHANOL INTOXICATION
CLINICAL USES OF ETHANOL
TOLERANCE, DEPENDENCE, AND CHRONIC ETHANOL USE
Etiology of Alcohol Use Disorders and the Role of Genes
Table 23-2 Genes for Intermediate Phenotypes Affecting Risk for Alcohol Use Disorder
TERATOGENIC EFFECTS: FETAL ALCOHOL SYNDROME
PHARMACOTHERAPY OF ALCOHOLISM
Naltrexone
Table 23-3 Oral Medications for Treating Alcohol Abuse
Acamprosate
Disulfiram
Other Agents
BIBLIOGRAPHY
chapter 24 Drug Addiction
Origins of Substance Dependence
Table 24-1 Multiple Simultaneous Variables Affecting Onset and Continuation of Drug Abuse and Addiction
Table 24-2 Dependence among Users 1990-1992
Pharmacological Phenomena
Figure 24-1. Shifts in a dose-response curve with tolerance and sensitization. With tolerance, there is a shift of the curve to the right such that doses higher than initial doses are required to achieve the same effects. With sensitization, there is a leftward shift of the curve such that for a given dose, there is a greater effect than seen after the initial dose.
Table 24-3 Types of Tolerance
Figure 24-2. Cocaine-induced changes in CNS dopamine release. Dopamine was measured in the extracellular fluid of the nucleus accumbens of rats after daily injections of cocaine (10 mg/kg, i.p.). The first injection of cocaine produced a modest increase and the last, after 7 days, produced a much greater increase in dopamine release. The first saline injection produced no effect on dopamine levels, whereas the second, given 3 days after 7 days of cocaine injections, produced a significant rise in dopamine, presumably due to conditioning. (Adapted from Kalivas and Duffy, 1990.)
Physical Dependence
CLINICAL ISSUES
CNS Depressants
Table 24-4 Alcohol Withdrawal Syndrome
Pharmacological Interventions.
Table 24-5 Benzodiazepine Withdrawal Symptoms
Nicotine
Table 24-6 Nicotine Withdrawal Symptoms
Figure 24-3. Nicotine concentrations in blood resulting from five different nicotine delivery systems. Shaded areas (upper panel) indicate the periods of exposure to nicotine. Arrows (lower panel) indicate when the nicotine patch was put on and taken off. (From Benowitz et al., 1988, and Srivastava et al, 1991, with permission. Benowitz et al, 1988 Copyright © Macmillan Publishers Ltd. Srivastava et al, 1991 Copyright © Springer Science and Business Media.)
Opioids
Figure 24-4. Differences in responses to heroin and methadone. A person who injects heroin (↑) several times per day oscillates (red line) between being sick and being high. In contrast, the typical methadone patient (purple line) remains in the "normal" range (indicated in blue) with little fluctuation after dosing once per day. The ordinate values represent the subject's mental and physical state, not plasma levels of the drug.
Table 24-7 Characteristics of Opioid Withdrawal
Cocaine and Other Psychostimulants
Table 24-8 Cocaine Withdrawal Symptoms and Signs
Cannabinoids (Marijuana)
Psychedelic Agents
Table 24-9 Marijuana Withdrawal Syndrome
Inhalants
CLINICAL SUMMARY
BIBLIOGRAPHY
Section III MODULATION OF CARDIOVASCULAR FUNCTION
chapter 25 Regulation of Renal Function and Vascular Volume
RENAL ANATOMY AND PHYSIOLOGY
(25-1)
(25-2)
Figure 25-1. Anatomy and nomenclature of the nephron.
Figure 25-2. Seven basic mechanisms for transmembrane transport of solutes. 1. Convective flow in which dissolved solutes are "dragged" by bulk water flow. 2. Simple diffusion of lipophilic solute across the membrane. 3. Diffusion of solute through a pore. 4. Transport of solute by carrier protein down electrochemical gradient. 5. transport of solute by carrier protein against an electrochemical gradient with ATP hydrolysis providing driving force. 6,7. Co-transport and countertransport, respectively, of solutes, with one solute traveling uphill against an electrochemical gradient and the other solute traveling down an electrochemical gradient.
Figure 25-3. Generic mechanism of renal epithelial cell transport (see text for details). S, symporter; A, antiporter; CH, ion channel; WP, water pore; U, uniporter; ATPase, Na+,K+-ATPase (sodium pump); X and Y, transported solutes; P, membrane-permeable (reabsorbable) solutes; I, membrane-impermeable (nonreabsorbable) solutes; PD, potential difference across indicated membrane or cell.
Figure 25-4. Mechanisms of organic acid (A) and organic base (B) secretion in the proximal tubule. The numbers 1, 2, and 3 refer to primary, secondary, and tertiary active transport. A−, organic acid [anion]; C+, organic base [cation]; αKG2−, α-ketoglutarate but also other dicarboxylates. BL and LM indicate basolateral and luminal membranes, respectively.
PRINCIPLES OF DIURETIC ACTION
Figure 25-5. Changes in extracellular fluid volume and weight with diuretic therapy. The period of diuretic administration is shown in the shaded box along with its effects on body weight in the upper part of the figure and Na+ excretion in the lower half of the figure. Initially, when Na+ excretion exceeds intake, body weight and extracellular fluid volume (ECFV) decrease. Subsequently, a new steady state is achieved where Na+ intake and excretion are equal but at a lower ECFV and body weight. This results from activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS), "the braking phenomenon." When the diuretic is discontinued, body weight and ECFV rise during a period where Na+ intake exceeds excretion. A new steady state is then reached as stimulation of the RAAS and SNS wane.
INHIBITORS OF CARBONIC ANHYDRASE
Table 25-1 Excretory and Renal Hemodynamic Effects of Diureticsa
Table 25-2 Inhibitors of Carbonic Anhydrase
Figure 25-6. NaHCO3 reabsorption in proximal tubule and mechanism of diuretic action of carbonic anhydrase inhibitors. The actual reaction catalyzed by carbonic anhydrase is OH− + CO2 → HCO3−; however, H2O → OH− + H+, and HCO3− + H+ → H2CO3, so the net reaction is H2O + CO2 → H2CO3. Numbers in parentheses indicate stoichiometry. A, antiporter; S, symporter; CH, ion channel; BL, basolateral membrane; LM, luminal membrane.
OSMOTIC DIURETICS
Table 25-3 Osmotic Diuretics
INHIBITORS OF Na+-K+-2Cl− SYMPORT (LOOP DIURETICS, IGH-CEILING DIURETICS)
Table 25-4 Inhibitors of Na+-K+-2Cl− Symport (Loop Diuretics, High-Ceiling Diuretics)
Figure 25-7. NaCl reabsorption in thick ascending limb and mechanism of diuretic action of Na+-K+-2Cl symport inhibitors. Numbers in parentheses indicate stoichiometry. Designated voltages are the potential differences across the indicated membrane or cell. The mechanisms illustrated here apply to the medullary, cortical, and postmacular segments of the thick ascending limb. S, symporter; CH, ion channel; BL, basolateral membrane; LM, luminal membrane.
INHIBITORS OF Na+-Cl− SYMPORT (THIAZIDE AND THIAZIDE-LIKE DIURETICS)
Figure 25-8. Dose-response curve of furosemide in chronic kidney disease. With chronic kidney disease the dose-response curve of furosemide and other loop diuretics shifts to the right. This may occur as a result of impaired proximal tubular secretion of the diuretic into the tubular lumen. This can occur for at least two reasons: (1) competition for peritubular uptake and luminal secretion by organic anions that accumulate in uremia such as urate and (2) metabolic acidosis.
Table 25-5 Inhibitors of Na+-Cl− Symport (thiazide and Thiazide-like Diuretics)
Figure 25-9. NaCl reabsorption in distal convoluted tubule and mechanism of diuretic action of Na+-Cl− symport inhibitors. Numbers in parentheses indicate stoichiometry. S, symporter; CH, ion channel; BL, basolateral membrane; LM, luminal membrane.
Table 25-6 Inhibitors of Renal Epithelial Na+ Channels (K+-Sparing Diuretics)
INHIBITORS OF RENAL EPITHELIAL Na+ CHANNELS (K+-SPARING DIURETICS)
Figure 25-10. Na+ reabsorption in late distal tubule and collecting duct and mechanism of diuretic action of epithelial Na+-channel inhibitors. Cl− reabsorption (not shown) occurs both paracellularly and transcellularly, and the precise mechanism of Cl− transport appears to be species-specific. Numbers in parentheses indicate stoichiometry. Designated voltages are the potential differences across the indicated membrane or cell. A, antiporter; CH, ion channel; CA, carbonic anhydrase; BL, basolateral membrane; LM, luminal membrane.
ANTAGONISTS OF MINERALOCORTICOID RECEPTORS (ALDOSTERONE ANTAGONISTS, K+-SPARING DIURETICS)
Table 25-7 Mineralocorticoid Receptor Antagonists (Aldosterone Antagonists, Potassium-Sparing Diuretics)
Figure 25-11. Effects of aldosterone on late distal tubule and collecting duct and diuretic mechanism of aldosterone antagonists. A. Cortisol also has affinity for the mineralocorticoid receptor (MR), but is inactivated in the cell by 11-β-hydroxysteroid dehydrogenase (HSD) type II. B. Serum and glucorticoid-regulated kinase (SGK)-1 is upregulated after ~30 minutes by aldosterone. SGK-1 phosphorylates and inactivates Nedd4-2 a ubiquitin-protein ligase that acts on ENaC, leading to its degradation. Phosphorylated Nedd4-2 no longer interacts with the PY motif of ENaC. As a result, the protein is not ubiquitinated and remains in the membrane, the end result of which is increased Na+ entry into the cell. 1. Activation of membrane-bound Na+ channels. 2. Na+ channel (ENaC) removal from the membrane is inhibited. 3. De novo synthesis of Na+ channels. 4. Activation of membranebound Na+,K+-ATPase. 5. Redistribution of Na+,K+-ATPase from cytosol to membrane. 6. De novo synthesis of Na+,K+-ATPase. 7. Changes in permeability of tight junctions. 8. Increased mitochondrial production of ATP. AIP, aldosterone-induced proteins; ALDO, aldosterone; MR, mineralocorticoid receptor; CH, ion channel; BL, basolateral membrane; LM, luminal membrane.
INHIBITORS OF THE NONSPECIFIC CATION CHANNEL: ATRIAL NATRIURETIC PEPTIDES
Figure 25-12. Inner medullary collecting duct (IMCD) Na+ transport and its regulation. Na+ enters the IMCD cell in one of two ways. The first is via ENaC, and the second is through a cyclic nucleotide gated nonspecific cation channel (CNGC) that transports Na+, K+, and NH4+ and is gated by cyclic GMP. Na+ then exits the cell via the Na+, K+-ATPase. It is the CNGC that is the primary pathway for Na+ entry, and is inhibited by natriuretic peptides. Atrial natriuretic peptides (ANP) bind to surface receptors (natriuretic peptide receptors A, B, and C). The A and B receptors are isoforms of particulate guanylate cyclase that catalyze the conversion of GTP to cyclic GMP. Cyclic GMP inhibits the CNGC directly, and indirectly through PKG. PKG activation also inhibits Na+ exit via the Na+, K+-ATPase.
CLINICAL USE OF DIURETICS
Figure 25-13. Summary of the site and mechanism of action of diuretics. Three important features of this summary figure are worth special note. 1. Transport of solute across epithelial cells in all nephron segments involves highly specialized proteins, which for the most part are apical and basolateral membrane integral proteins. 2. Diuretics target and block the action of epithelial proteins involved in solute transport. 3. The site and mechanism of action of a given class of diuretics are determined by the specific protein inhibited by the diuretic. CA, carbonic anhydrase; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; Aldo, aldosterone.
Figure 25-14. Interrelationships among renal function, Na+ intake, water homeostasis, distribution of extracellular fluid volume, and mean arterial blood pressure. Pathophysiological mechanisms of edema formation. 1. Rightward shift of renal pressure natriuresis curve. 2. Excessive dietary Na+ intake. 3. Increased distribution of extracellular fluid volume (ECFV) to peritoneal cavity (e.g., liver cirrhosis with increased hepatic sinusoidal hydrostatic pressure) leading to ascites formation. 4. Increased distribution of ECFV to lungs (e.g., left-sided heart failure with increased pulmonary capillary hydrostatic pressure) leading to pulmonary edema. 5. Increased distribution of ECFV to venous circulation (e.g., right-sided heart failure) leading to venous congestion. 6. Peripheral edema caused by altered Starling forces causing increased distribution of ECFV to interstitial space (e.g., diminished plasma proteins in nephrotic syndrome, severe burns, and liver disease).
Figure 25-15. "Brater's algorithm" for diuretic therapy of chronic renal failure, nephrotic syndrome, congestive heart failure, and cirrhosis. Follow algorithm until adequate response is achieved. If adequate response is not obtained, advance to the next step. For illustrative purposes, the thiazide diuretic used in Brater's algorithm is hydrochlorothiazide (HCTZ). An alternative thiazide-type diuretic may be substituted with appropriate dosage adjustment so as to be pharmacologically equivalent to the recommended dose of HCTZ. Do not combine two K+-sparing diuretics because of the risk of hyperkalemia. CrCl indicates creatinine clearance in mL/min, and ceiling dose refers to the smallest dose of diuretic that produces a near-maximal effect. Ceiling doses of loop diuretics and dosing regimens for continuous intravenous infusions of loop diuretics are disease-state-specific. In this regard, see Brater (1998) for recommended dosages. Doses are for adults only.
WATER HOMEOSTASIS
INTRODUCTION TO VASOPRESSIN
PHYSIOLOGY OF VASOPRESSIN
Figure 25-16. Processing of the 168-amino acid human 8-arginine vasopressin (AVP) preprohormone to AVP, vasopressin (VP)-neurophysin, and VP-glycopeptide. More than 40 mutations in the single gene on chromosome 20 that encodes AVP preprohormone give rise to central diabetes insipidus. *Boxes indicate mutations leading to central diabetes insipidus.
Figure 25-17. A. The relationship between plasma osmolality and plasma vasopressin levels. Plasma osmolality range associated with thirst is indicated by arrow. B. The relationship between plasma vasopressin levels and urine osmolality. (From Robertson et al., 1977, and Kovacs and Robertson, 1992, with permission. Copyright © Elsevier.)
Figure 25-18. Interactions between osmolality and hypovolemia/hypotension. Numbers in circles refer to percentage increase (+) or decrease (−) in blood volume or arterial blood pressure. N indicates normal blood volume/blood pressure. (Reprinted by permission from Macmillan Publishers Ltd: Robertson GL, Shelton RL, Athar S: The osmoregulation of vasopressin. Kidney Internat 10:25, 1976. Copyright © 1976.)
BASIC PHARMACOLOGY OF VASOPRESSIN
Figure 25-19. Mechanism of V1 receptor-effector coupling. Binding of 8-arginine vasopressin (AVP) to V1 vasopressin receptors (V1) stimulates several membrane-bound phospholipases. Stimulation of the Gq-PLCβ pathway results in IP3 formation, mobilization of intracellular Ca2+, and activation of PKC. Activation of V1 receptors also causes influx of extracellular Ca2+ by an unknown mechanism. PKC and Ca2+/calmodulin-activated protein kinases phosphorylate cell-type-specific proteins leading to cellular responses. A further component of the AVP response derives from the production of eicosanoids secondary to the activation of PLA2; the resulting mobilization of arachidonic acid (AA) provides substrate for eicosanoid synthesis by the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, leading to local production of prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT), which may activate a variety of signaling pathways, including those linked to GS and Gq. Biological effects mediated by the V1 receptor include vasoconstriction, glycogenolysis, platelet aggregation, ACTH release, and growth of vascular smooth muscle cells. The effects of vasopressin on cell growth involve transcriptional regulation by the FOS/JUN AP-1 transcription complex.
Figure 25-20. Mechanism of V2 receptor-effector coupling. Binding of vasopressin (AVP) to the V2 receptor activates the GS-adenylyl cyclase-cAMP-PKA pathway and shifts the balance of aquaporin 2 trafficking toward the apical membrane of the principal cell of the collecting duct, thus enhancing water permeability. Although phosphorylation of serine 256 of aquaporin 2 is involved in V2 receptor signaling, other proteins located both in the water channel-containing vesicles and the apical membrane of the cytoplasm also may be involved.
Figure 25-21. Structure of aquaporins. Aquaporins have six transmembrane domains, and the NH2 and COOH termini are intracellular. Loops B and E each contain an asparagine-proline-alanine (NPA) sequence. Aquaporins fold with transmembrane domains 1, 2, and 6 in close proximity and transmembrane domains 3, 4 and 5 in juxtaposition. The long B and E loops dip into the membrane, and the NPA sequences align to create a pore through which water can diffuse. Most likely aquaporins form a tetrameric oligomer. At least seven aquaporins are expressed at distinct sites in the kidney. Aquaporin 1, abundant in the proximal tubule and descending thin limb, is essential for concentration of urine. Aquaporin 2, exclusively expressed in the principal cells of the connecting tubule and collecting duct, is the major vasopressin-regulated water channel. Aquaporin 3 and aquaporin 4 are expressed in the basolateral membranes of collecting-duct principal cells and provide exit pathways for water reabsorbed apically by aquaporin 2. Aquaporin 7 is in the apical brush border of the straight proximal tubule. Aquaporins 6 to 8 are also expressed in kidney; their functions remain to be clarified. Vasopressin regulates water permeability of the collecting duct by influencing the trafficking of aquaporin 2 from intracellular vesicles to the apical plasma membrane (Figure 25-20). AVP-induced activation of the cAMP-PKA pathway also enhances expression of aquaporin 2 mRNA and protein; chronic dehydration thus causes up-regulation of aquaporin 2 and water transport in the collecting duct.
Figure 25-22. Mechanisms by which vasopressin increases the renal conservation of water. Red and black arrows denote major and minor pathways, respectively. IMCD, inner medullary collecting duct; TAL, thick ascending limb; VRUT, vasopressinregulated urea transporter.
VASOPRESSIN RECEPTOR AGONISTS AND ANTAGONISTS
Table 25-8 Vasopressin Receptor Agonists
DISEASES AFFECTING THE VASOPRESSIN SYSTEM
CLINICAL PHARMACOLOGY OF VASOPRESSIN PEPTIDES
Agonists
Vasopressin Receptor Antagonists
Pharmacokinetics
Toxicity, Adverse Effects, Contraindications, Drug Interactions
Table 25-9 Vasopressin Receptor Antagonists
Future Directions in Vasopressin Analogs
BIBLIOGRAPHY
chapter 26 Renin and Angiotensin
THE RENIN-ANGIOTENSIN SYSTEM
Components of the Renin-Angiotensin System
Figure 26-1. Components of the RAS. The heavy arrows show the classical pathway, and the light arrows indicate alternative pathways. ACE, angiotensin-converting enzyme; Ang, angiotensin; AP, aminopeptidase; E, endopeptidases; IRAP, insulin-regulated amino peptidases; PCP, prolylcarboxylpeptidase; PRR, (pro)renin receptor. Receptors involved: AT1, AT2, Mas, AT4, and PRR. *Exposure of the active site of renin can also occur non-proteolytically; see text and Figure 26-3.
Figure 26-2. A. Schematic portrayal of the three major physiological pathways regulating renin release. See text for details. MD, macula densa; PGI2/PGE2 prostaglandins I2 and E2; NSAIDs, nonsteroidal antiinflammatory drugs; Ang II, angiotensin II: ACE, angiotensin-converting enzyme. AT1 R, angiotensin subtype 1 receptor; NE/Epi, norepinephrine/epinephrine; JGCs, juxtaglomerular cells. B. Mechanisms by which the macula densa regulates renin release. Changes in tubular delivery of NaCl to the macula densa cause appropriate signals to be conveyed to the juxtaglomerular cells. Sodium depletion upregulates nNOS and COX-2 in the macula densa to enhance production of prostaglandins (PGs). PGs and catecholamines stimulate cyclic AMP production and thence renin release from the juxtaglomerular cells. Increased NaCl transport depletes ATP and increases adenosine (ADO) levels. Adenosine diffuses to the juxtaglomerular cells and inhibits cyclic AMP production and renin release via Gi-coupled A1 receptors. Increased NaCl transport in the macula densa augments the efflux of ATP, which may inhibit renin release directly by binding to P2Y receptors and activating the Gq-PLC-IP3-Ca2+ pathway in juxtaglomerular cells. Circulating AngII also inhibits renin release on juxtaglomerular cells via Gq-coupled AT1 receptors.
Figure 26-3. Biological activation of prorenin and pharmacological inhibition of renin. Pro-renin (black segment) is inactive; accessibility of angiotensinogen (AGT) to the active is blocked by the propeptide (black segment). The blocked catalytic site can be activated non-proteolytically by the binding of prorenin to the (pro) renin receptor (PRR) or by proteolytic removal of the propeptide. The competitive renin inhibitor, aliskiren, has a higher affinity (~0.1µm) for the active site of renin than does AGT (~1 µm).
Figure 26-4. Ang II-dependent and Ang II-independent actions of prorenin. See text for details.
Functions and Effects of the Renin-Angiotensin System
Figure 26-5. Effect of a bolus intravenous injection of AngII (0.05 µg/kg) on arterial blood pressure (BP) and renal blood flow (RBF) in a conscious dog. (Reproduced with permission, from Zimmerman BG. Absence of adrenergic mediation of agonist response to [Sar1,Ala8] angiotensin II in conscious normotensive and hypertensive dogs. Clin Sci, 1979, 57:71–81. © the Biochemical Society.)
Figure 26-6. Summary of the three major effects of AngII and the mechanisms that mediate them. NE, norepinephrine.
Rapid Pressor Response
Slow Pressor Response
Figure 26-7. Pressure-natriuresis curve: effects of Na+ intake on renin release (AngII formation) and arterial blood pressure. Inhibition of the renin-angiotensin system will cause a large drop in blood pressure in Na+-depleted individuals. (Modified with permission from Jackson EK, Branch RA, et al: Physiological functions of the renal prostaglandin, renin, and kalikrein systems, in Seldin DW, Giebisch GH, eds: The Kidney: Physiology and Pathophysiology, Vol 1. Philadelphia: Lippincott Williams & Wilkins, 1985, p 624. http://lww.com.)
Angiotensin and Vascular Disease
INHIBITORS OF THE RENIN-ANGIOTENSIN SYSTEM
Figure 26-8. Inhibitors of the RAS. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; DRI, direct renin inhibitor.
Angiotensin-Converting Enzyme Inhibitors
Figure 26-9. Chemical structures of selected ACE inhibitors. Captopril, lisinopril, and enalaprilat are active molecules. Benazepril, enalapril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are relatively inactive until converted to their corresponding diacids. The structures enclosed within red boxes are removed by esterases and replaced with a hydrogen atom to form the active molecule in vivo (e.g., enalapril to enalaprilat or ramipril to ramiprilat).
NON-PEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS
Figure 26-10. AngII receptor antagonists. Structures within red boxes are removed by esterases and replaced with a hydrogen atom to form the active molecule in vivo. "~" indicates point of attachment to biphenyl core.
DIRECT RENIN INHIBITORS
Table 26-1 Effects of Anti-hypertensive Agents on Components of the RAS
Pharmacological Lowering of Blood Pressures Alters Components of the RAS
BIBLIOGRAPHY
chapter 27 Treatment of Myocardial Ischemia and Hypertension
PATHOPHYSIOLOGY OF ISCHEMIC HEART DISEASE
Figure 27-1. Pharmacological modification of the major determinants of myocardial O2 supply. When myocardial O2 requirements exceed O2 supply, an ischemic episode results. This figure shows the primary hemodynamic sites of actions of pharmacological agents that can reduce O2 demand (left side) or enhance O2 supply (right side). Some classes of agents have multiple effects. Stents, angioplasty, and coronary bypass surgery are mechanical interventions that increase O2 supply. Both pharmacotherapy and mechanotherapy attempt to restore a dynamic balance between O2 demand and O2 supply.
ORGANIC NITRATES
Pharmacological Properties
Table 27-1 Organic Nitrates Available for Clinical Use
Preparations
Tolerance
Toxicity and Untoward Responses
Therapeutic Uses
Ca2+ CHANNEL ANTAGONISTS
Table 27-2 Ca2+ Channel Blockers: Chemical structures and Some Relative Cardiovascular Effectsa
Pharmacological Properties
Therapeutic Uses
β ADRENERGIC RECEPTOR ANTAGONISTS
Therapeutic Uses
COMPARISON OF ANTI-ANGINAL THERAPEUTIC STRATEGIES
Table 27-3 Recommended Drug Therapy for Angina in Patients with Other Medical Conditions
ANTI-PLATELET, ANTI-INTEGRIN, AND ANTI-THROMBOTIC AGENTS
TREATMENT OF CLAUDICATION AND PERIPHERAL VASCULAR DISEASE
MECHANO-PHARMACOLOGICAL THERAPY: DRUG-ELUTING ENDOVASCULAR STENTS
THERAPY OF HYPERTENSION
Table 27-4 Criteria for Hypertension in Adults
Table 27-5 Classification of Antihypertensive Drugs by Their Primary Site or Mechanism of Action
DIURETICS
Table 27-6 Hemodynamic Effects of Long-Term Administration of Antihypertensive Agents
Benzothiadiazines and Related Compounds
Other Diuretic Antihypertensive Agents
Diuretic-Associated Drug Interactions
SYMPATHOLYTIC AGENTS
β Adrenergic Receptor Antagonists
α1 Adrenergic Receptor Antagonists
COMBINED α1 AND β ADRENERGIC RECEPTOR ANTAGONISTS
Methyldopa
Clonidine, Guanabenz, and Guanfacine
Guanadrel
Reserpine
Metyrosine
Ca2+ CHANNEL ANTAGONISTS
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
AT1 RECEPTOR ANTAGONISTS
DIRECT RENIN INHIBITORS
VASODILATORS
Hydralazine
KATP Channel Openers: Minoxidil
Sodium Nitroprusside
NONPHARMACOLOGICAL THERAPY OF HYPERTENSION
SELECTION OF ANTIHYPERTENSIVE DRUGS IN INDIVIDUAL PATIENTS
RESISTANT HYPERTENSION
BIBLIOGRAPHY
chapter 28 Pharmacotherapy of Congestive Heart Failure
PHARMACOLOGIC TREATMENT OF HEART FAILURE
Diuretics
Figure 28-1. Pathophysiologic mechanisms of heart failure and major sites of drug action. Congestive heart failure is accompanied by compensatory neurohormonal responses, including activation of the sympathetic nervous and renin-angiotensin-aldosterone axis. Increased ventricular afterload, due to systemic vasoconstriction and chamber dilation, causes depression in systolic function. In addition, increased afterload and the direct effects of angiotensin and norepinephrine on the ventricular myocardium cause pathologic remodeling characterized by progressive chamber dilation and loss of contractile function. Key congestive heart failure medications and their targets of action are presented. ACE, angiotensin-converting enzyme; AT1 receptor, type 1 angiotensin receptor.
Figure 28-2. Hemodynamic responses to pharmacologic interventions in heart failure. The relationships between diastolic filling pressure (preload) and stroke volume (ventricular performance) are illustrated for a normal heart (green line; the Frank-Starling relationship) and for a patient with heart failure due to predominant systolic dysfunction (red line). Note that positive inotropic agents (I), such as cardiac glycosides or dobutamine, move patients to a higher ventricular function curve (lower dashed line), resulting in greater cardiac work for a given level of ventricular filling pressure. Vasodilators (V), such as angiotensin-converting enzyme (ACE) inhibitors or nitroprusside, also move patients to improved ventricular function curves while reducing cardiac filling pressures. Diuretics (D) improve symptoms of congestive heart failure by moving patients to lower cardiac filling pressures along the same ventricular function curve.
Table 28-1 Causes of Diuretic Resistance in Heart Failure
Aldosterone Antagonists and Clinical Outcome
Vasodilators
Figure 28-3. The renin-angiotensin-aldosterone axis. Renin, excreted in response to β adrenergic stimulation of the juxtaglomerular (J-g) cells of the kidney, cleaves plasma angiotensinogen to produce angiotensin I. Angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II (AngII). Most of the known biologic effects of AngII are mediated by the type 1 angiotensin (AT1) receptor. In general, the AT2 receptor appears to counteract the effects of AngII that are mediated by activation of the AT1 pathway. AngII also may be formed through ACE-independent pathways. These pathways, and possibly incomplete inhibition of tissue ACE, may account for persistence of Ang II in patients treated with ACE inhibitors. ACE inhibition decreases bradykinin degradation, thus enhancing its levels and biologic effects, including the production of NO and PGI2. Bradykinin may mediate some of the biological effects of ACE inhibitors.
Table 28-2 Potential Roles of Aldosterone in the Pathophysiology of Heart Failure
Table 28-3 Vasodilator Drugs Used to Treat Heart Failure
Parenteral Vasodilators
Figure 28-4. Relationship between ventricular outflow resistance and stroke volume in patients with systolic ventricular dysfunction. An increase in ventricular outflow resistance, a principal determinant of afterload, has little effect on stroke volume in normal hearts, as illustrated by the relatively flat curve. In contrast, in patients with systolic ventricular dysfunction, an increase in outflow resistance often is accompanied by a sharp decline in stroke volume. With more severe ventricular dysfunction, this curve becomes steeper. Because of this relationship, a reduction in systemic vascular resistance (one component of outflow resistance) in response to an arterial vasodilator may markedly increase stroke volume in patients with severe myocardial dysfunction. The resultant increase in stroke volume may be sufficient to offset the decrease in systemic vascular resistance, thereby preventing a fall in systemic arterial pressure. (Adapted with permission from Cohn and Franciosa, 1977. Copyright © Massachusetts Medical Society. All rights reserved.)
Targeting Neurohormonal Regulation: The Renin-Angiotensin-Aldosterone Axis and Vasopressin Antagonists
β Adrenergic Receptor Antagonists
Clinical Use of β Adrenergic Receptor Antagonists in Heart Failure
Cardiac Glycosides
Figure 28-5. Sarcolemmal exchange of Na+ and Ca2+ during cell depolarization and repolarization. Na+ and Ca2+ enter the cardiac myocyte via the Na+ channel and the L-type Ca2+ channel during each cycle of membrane depolarization, triggering the release, through the ryanodine receptor (RyR), of larger amounts of Ca2+ from internal stores in the sarcoplasmic reticulum (SR). The resulting increase in intracellular Ca2+ interacts with troponin C and activates interactions between actin and myosin that result in sarcomere shortening. The electrochemical gradient for Na+ across the sarcolemma is maintained by active transport of Na+ out of the cell by the sarcolemmal Na+,K+-ATPase. The bulk of cytosolic Ca2+ is pumped back into the SR by a Ca2+-ATPase, SERCA2. The remainder is removed from the cell by either a sarcolemmal Ca2+-ATPase or a high-capacity Na+-Ca2+ exchanger, NCX. NCX exchanges 3 Na+ for every Ca2+, using the electrochemical potential of Na+ to drive Ca2+ extrusion. The direction of Na+-Ca2+ exchange may reverse briefly during depolarization, when the electrical gradient across the sarcolemma is transiently reversed. β adrenergic agonists and PDE inhibitors, by increasing intracellular cyclic AMP levels, activate PKA, which phosphorylates phospholamban (PL), the α subunit of the L-type Ca2+ channel, and regulatory components of the RyR, as well as TnI, the inhibitory subunit of troponin (not shown). As a result, the probabilities of opening of the L-type Ca2+ channel and the RyR2 Ca2+ channel are doubled; SERCA2 is uninhibited and accumulates Ca2+ into the SR faster, more avidly, and to a higher concentration; and relaxation occurs at slightly higher [Ca2+]i due to slightly reduced sensitivity of the troponin complex to Ca2+. The net effect of these phosphorylations is a positive inotropic effect: a faster rate of tension development to a higher level of tension, followed by a faster rate of relaxation. ▴ indicates site of cardiac glycoside binding. See the text for the mechanism of positive inotropic effect of cardiac glycosides.
β Adrenergic and Dopaminergic Agonists
Chronic Positive Inotropic Therapy
Diastolic Heart Failure
Figure 28-6. Pressure-volume relationships in normal heart and heart with diastolic dysfunction. Normal P-V loo (green) based on normal end diastolic pressure-volume relationship (EDPVR). P-V loop with diastolic dysfunction is shown in red. ESPVR, end-systolic pressure- volume relationship.
Future Therapies: Targeting Vascular Dysfunction in Congestive Heart Failure from Systolic Dysfunction
Figure 28-7. Preserving normal vascular reactivity is a target of evolving priority in the treatment of patients with chronic congestive heart failure. Increased levels of reactive oxygen species (ROS), including superoxide (O2−) and hydrogen peroxide (H2O2) that are generated in both endothelial cells (EC) and vascular smooth muscle cells (VSMC) impair key cell signaling pathways necessary for normal vascular function. Specifically, hyperaldosterone-induced decreased antioxidant enzyme activity in EC, such as glucose-6-phosphate dehydrogenase (G6PD), results in increased ROS formation (Leopold et al., 2007). Likewise, increased xanthine oxidase (XO) activity, AT1 receptor activation, and upregulation of signaling pathways associated with cholesterol metabolism create a cellular environment favorable for ROS formation. In EC, elevated levels of ROS impair vascular reactivity, in part, by decreasing endothelial nitric oxide synthase (eNOS) activity and increasing peroxynitrite (ONOO−) formation to decrease bioavailable nitric oxide (NO) levels. In VSMC, oxidant stress decreases NO levels and impairs soluble guanylyl cyclase (sGC) sensitivity to NO, thereby decreasing cyclic GMP levels that are necessary for normal VSMC relaxation. Mineralacorticoid (MR)-receptor antagonists, XO inhibitors (XO-I), HMG-coA-reductase inhibitors (statin), AT1 receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors block various cellular reactions associated with elevated levels of ROS and impaired vascular reactivity. The BAY compounds (e.g., BAY 58-2667; figure inset), in turn, are a novel group of direct sGC activators that increase enzyme activity despite oxidant stress-induced sGC modifications that convert the enzyme to an NO-insensitive state. XO-I, xanthine oxidase inhibitor.
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 29 Anti-Arrhythmic Drugs
PRINCIPLES OF CARDIAC ELECTROPHYSIOLOGY
The Cardiac Cell at Rest: a K+-permeable membrane
Figure 29-1. Electrical and chemical gradients for K+ and Na+ in a resting cardiac cell. Inward rectifier K+ channels are open (left), allowing K+ ions to move across the membrane and the transmembrane potential to approach EK. In contrast, Na+ does not enter the cell despite a large net driving force because Na+ channel proteins are in the closed conformation (right) in resting cells.
The Cardiac Action Potential
Figure 29-2. Voltage dependent conformational changes determine current flow through Na+ channels. At hyperpolarized potentials, the channel is in a closed conformation and no current can flow (left). As depolarization begins, the pore opens, allowing conduction (middle). And finally, as depolarization is maintained, an intracellular particle blocks current flow, making the channel non-conducting in this inactivated state (right).
Figure 29-3. The relationship between an action potential from the conducting system and the time course of the currents that generate it. The current magnitudes are not to scale; the Na+ current is ordinarily 50 times larger than any other current, although the portion that persists into the plateau (phase 2) is small. Multiple types of Ca2+ current, transient outward current (ITO), and delayed rectifier (IK) have been identified. Each represents a different channel protein, usually associated with ancillary (function-modifying) subunits. 4-AP (4-aminopyridine) is a widely used in vitro blocker of K+ channels. ITO2 may be a Cl- current in some species. Components of IK have been separated on the basis of how rapidly they activate: slowly (IKs), rapidly (IKr), or ultra-rapidly (IKur). The voltage-activated, time-independent current may be carried by Cl- (ICl) or K+ (IKp, p for plateau). The genes encoding the major pore-forming proteins have been cloned for most of the channels shown here and are included in the right-hand column. The righthand column lists the primary genes that code for the various ion channels and transporters.
Action Potential Heterogeneity in the Heart
Figure 29-4. Normal impulse propagation. A schematic of the human heart with example action potentials from different regions of the heart (top) for a normal beat and their corresponding contributions to the macroscopic ECG (bottom). AV, atrioventricular; LV, left ventricle; RV, right ventricle; SA, sinoatrial. (Used with permission from The Am Physiol Soc. Nerbonne and Kass, Physiol Rev, 2005.)
Maintenance of Intracellular Ion Homeostasis
Impulse Propagation and the Electrocardiogram
Refractoriness and Conduction Failure
Figure 29-5. Qualitative differences in responses of nodal and conducting tissues to premature stimuli. A. With a very early premature stimulus (black arrow) in ventricular myocardium, all Na+ channels still are in the inactivated state, and no upstroke results. As the action potential repolarizes, Na+ channels recover from the inactivated to the resting state, from which opening can occur. The phase 0 upstroke slope of the premature action potentials (purple) are greater with later stimuli because recovery from inactivation is voltage dependent. B. The relationship between transmembrane potential and degree of recovery of Na+ channels from inactivation. The dotted line indicates 25% recovery. Most Na+ channel-blocking drugs shift this relationship to the left. C. In nodal tissues, premature stimuli delivered even after full repolarization of the action potential are depressed; recovery from inactivation is time dependent.
MECHANISMS OF CARDIAC ARRHYTHMIAS
Enhanced Automaticity
Afterdepolarizations and Triggered Automaticity
Re-entry
Table 29-1 Drug-Induced Cardiac Arrhythmias
Figure 29-6. Afterdepolarizations and triggered activity. A. Delayed afterdepolarization (DAD) arising after full repolarization. DADs are typically caused by spontaneous Ca2+ release from the sarcoplasmic reticulum under conditions of Ca2+ overload. The extra cytosolic Ca2+ is removed from the cytosol by the electrogenic Na-Ca exchanger (NCX), which produces Na+ influx and causes a cell membrane depolarization in the form of a DAD. A DAD that reaches threshold results in a triggered upstroke (black arrow, right). B. Early afterdepolarization (EAD) interrupting phase 3 repolarization. Multiple ion channels and transporters can contribute to EADs (e.g., Na+ channel, L-type Ca2+ channel, NCX). Under some conditions, triggered beat(s) can arise from an EAD (black arrow, right).
Figure 29-7. Atrioventricular re-entrant tachycardia in the Wolff-Parkinson-White syndrome. In these patients, an accessory atrioventricular (AV) connection is present (light blue). A premature atrial impulse blocks in the accessory pathway (1) and propagates slowly through the AV node and conducting system. On reaching the accessory pathway (by now no longer refractory), the impulse re-enters the atrium (2), where it then can re-enter the ventricle via the AV node and become self-sustaining (see Figure 29-9C). AV nodal blocking drugs readily terminate this tachycardia. Recurrences can be prevented by drugs that prevent atrial premature beats, by drugs that alter the electrophysiologic characteristics of tissue in the circuit (e.g., they prolong AV nodal refractoriness), and by nonpharmacologic techniques that section the accessory pathway.
Figure 29-8. Two types of re-entry. The border of a propagating wavefront is denoted by a heavy black arrowhead. In anatomically defined re-entry (top), a fixed pathway is present (e.g., Figure 29-7). The black area denotes tissue in the re-entrant circuit that is completely refractory because of the recent passage of the propagating wavefront; the gray area denotes tissue in which depressed upstrokes can be elicited (see Figure 29-5A), and the red area represents tissue in which restimulation would result in action potentials with normal upstrokes. The red area is termed an excitable gap. In functionally defined, or "leading circle," re-entry (bottom), there is no anatomic pathway and no excitable gap. Rather, the circulating wavefront creates an area of inexcitable tissue at its core. In this type of re-entry, the circuit does not necessarily remain in the same anatomic position during consecutive beats, and multiple such "rotors" may be present.
Common Arrhythmias and Their Mechanisms
MECHANISMS OF ANTI-ARRHYTHMIC DRUG ACTION
Table 29-2 A Mechanistic Approach to Anti-Arrhythmic Therapy
Figure 29-9. ECGs showing normal and abnormal cardiac rhythms. The P, QRS, and T waves in normal sinus rhythm are shown in panel A. Panel B shows a premature beat arising in the ventricle (arrow). Paroxysmal supraventricular tachycardia (PSVT) is shown in panel C; this most likely is re-entry using an accessory pathway (see Figure 29-7) or re-entry within or near the atrioventricular (AV) node. In atrial fibrillation (panel D), there are no P waves, and the QRS complexes occur irregularly (and at a slow rate in this example); electrical activity between QRS complexes shows small undulations (arrow) corresponding to fibrillatory activity in the atria. In atrial flutter (panel E), the atria beat rapidly, ~250 beats/minute (arrows) in this example, and the ventricular rate is variable. If a drug that slows the rate of atrial flutter is administered, 1:1 AV conduction (panel F) can occur. In monomorphic ventricular tachycardia (VT, panel G), identical wide QRS complexes occur at a regular rate, 180 beats/min. The electrocardiographic features of the torsades de pointes syndrome (panel H) include a very long QT interval (>600 ms in this example, arrow) and ventricular tachycardia in which each successive beat has a different morphology (polymorphic VT). Panel I shows the disorganized electrical activity characteristic of ventricular fibrillation.
Figure 29-10. Four ways to reduce the rate of spontaneous discharge. The blue horizontal line represents threshold potential.
Figure 29-11. Two ways to increase refractoriness. In this figure, the black dot indicates the point at which a sufficient number of Na+ channels (an arbitrary 25%; see Figure 29-5B) have recovered from inactivation to allow a premature stimulus to produce a propagated response in the absence of a drug. Block of Na+ channels (A) shifts voltage dependence of recovery (see Figure 29-5B) and so delays the point at which 25% of channels have recovered (red diamond), prolonging refractoriness. Note that if the drug also dissociates slowly from the channel (see Figure 29-12), refractoriness in fast-response tissues actually can extend beyond full repolarization ("postrepolarization refractoriness"). Drugs that prolong the action potential (B) also will extend the point at which an arbitrary percentage of Na+ channels have recovered from inactivation, even without directly interacting with Na+ channels. ERP, effective refractory period.
State-Dependent Ion Channel Block
Figure 29-12. Recovery from block of Na+ channels during diastole. This recovery is the critical factor determining extent of steadystate Na+ channel block. Na+ channel blockers bind to (and block) Na+ channels in the open and/or inactivated states, resulting in phasic changes in the extent of block during the action potential. As shown in the middle panel, a decrease in the rate of recovery from block increases the extent of block. Different drugs have different rates of recovery, and depolarization reduces the rate of recovery. The right panel shows that increasing heart rate, which results in relatively less time spent in the rest state, also increases the extent of block. (Modified from Roden et al., 1993, with permission from Wiley-Blackwell Publishing.)
Classifying Anti-Arrhythmic Drugs
Table 29-3 Major Electrophysiologic Actions of Anti-Arrhythmic Drugs
PRINCIPLES IN THE CLINICAL USE OF ANTI-ARRHYTHMIC DRUGS
1. Identify and Remove Precipitating Factors
2. Establish the Goals of Treatment
Table 29-4 Patient-Specific Anti-Arrhythmic Drug Contraindications
3. Minimize Risks
4. Consider the Electrophysiology of the Heart as a "Moving Target"
ANTI-ARRHYTHMIC DRUGS
Table 29-5 Pharmacokinetic Characteristics and Doses of Anti-Arrhythmic Drugs
Digoxin
BIBLIOGRAPHY
chapter 30 Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs
OVERVIEW OF HEMOSTASIS: PLATELET FUNCTION, BLOOD COAGULATION, AND FIBRINOLYSIS
Figure 30-1. Platelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogenbinding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2 (prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation.
Figure 30-2. Major reactions of blood coagulation. Shown are interactions among proteins of the "extrinsic" (tissue factor and factor VII), "intrinsic" (factors IX and VIII), and "common" (factors X, V, and II) coagulation pathways that are important in vivo. Boxes enclose the coagulation factor zymogens (indicated by Roman numerals); the rounded boxes represent the active proteases. TF, tissue factor. Activated coagulation factors are followed by the letter "a": II, prothrombin; IIa, thrombin.
Figure 30-3. Fibrinolysis. Endothelial cells secrete tissue plasminogen activator (t-PA) at sites of injury. t-PA binds to fibrin and converts plasminogen to plasmin, which digests fibrin. Plasminogen activator inhibitors-1 and -2 (PAI-1, PAI-2) inactivate t-PA; α2-antiplasmin (α2-AP) inactivates plasmin
PARENTERAL ANTICOAGULANTS
Heparin and Its Derivatives
Table 30-1 Comparison of the Features of Heparin, LMWH, and Fondaparinux
Figure 30-4. The antithrombin-binding pentasaccharide structure of heparin. Sulfate groups required for binding to antithrombin are indicated in red.
Figure 30-5. Mechanism of action of heparin, low-molecular-weight heparin (LMWH), and fondaparinux, a synthetic pentasaccharide. A. Heparin binds to antithrombin via its pentasaccharide sequence. This induces a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa. To potentiate thrombin inhibition, heparin must simultaneously bind to antithrombin and thrombin. Only heparin chains composed of at least 18 saccharide units (molecular weight ~5,400 Da) are of sufficient length to perform this bridging function. With a mean molecular weight of 15,000 Da, virtually all of the heparin chains are long enough to do this. B. LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin because at least half of the LMWH chains (mean molecular weight 4,500–5,000 Da) are too short to bridge antithrombin to thrombin. C. The pentasaccharide accelerates only factor Xa inhibition by antithrombin; the pentasaccharide is too short to bridge antithrombin to thrombin.
Toxicity and Adverse Events
Other Parenteral Anticoagulants
ORAL ANTICOAGULANTS
Warfarin
Figure 30-6. Structural formulas of the vitamin K antagonists. 4-Hydroxycoumarin and indan-1,3-dione are the parent molecules from which the vitamin K antagonists are derived. The asymmetrical carbon atoms in the coumarins are shown in red.
Figure 30-7. The vitamin K cycle and mechanism of action of warfarin. In the racemic mixture of S- and R-enantiomers, S-warfarin is more active. By blocking vitamin K epoxide reductase encoded by the VKORC1 gene, warfarin inhibits the conversion of oxidized vitamin K epoxide into its reduced form, vitamin K hydroquinone. This inhibits vitamin K-dependent γ-carboxylation of factors II, VII, IX, and X because reduced vitamin K serves as a cofactor for a γ-glutamyl carboxylase that catalyzes the γ-carboxylation process, thereby converting prozymogens to zymogens capable of binding Ca2+ and interacting with anionic phospholipid surfaces. S-warfarin is metabolized by CYP2C9. Common genetic polymorphisms in this enzyme can influence warfarin metabolism. Polymorphisms in the C1 subunit of vitamin K reductase (VKORC1) also can affect the susceptibility of the enzyme to warfarin-induced inhibition, thereby influencing warfarin dosage requirements.
Table 30-2 Frequencies of CYP2C9 Genotypes and VKORC1 Haplotypes in Different Populations and Their Effect on Warfarin Dose Requirements
Toxicities
Other Vitamin K Antagonists
NEW ORAL ANTICOAGULANTS
FIBRINOLYTIC DRUGS
Inhibitors of Fibrinolysis
Table 30-3 Absolute and Relative Contraindications to Fibrinolytic Therapy
ANTIPLATELET DRUGS
Figure 30-8. Sites of action of antiplatelet drugs. Aspirin inhibits thromboxane A2 (TxA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TxA2 release attenuates platelet activation and recruitment to the site of vascular injury. Ticlopidine, clopidogrel, and prasugrel irreversibly block P2Y12, a key ADP receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12. Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor (vWF) from binding to activated glycoprotein (GP) IIb/IIIa. SCH530348 and E5555 inhibit thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on platelets.
Figure 30-9. Structures of ticlopidine, clopidogrel, and prasugrel.
Table 30-4 Features of GPIIb/IIIa Antagonists
Newer Antiplatelet Agents
THE ROLE OF VITAMIN K
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 31 Drug Therapy for Hypercholesterolemia and Dyslipidemia
PLASMA LIPOPROTEIN METABOLISM
Table 31-1 Characteristics of Plasma Lipoproteins
Table 31-2 Apolipoproteins
Figure 31-1. The major pathways involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liver. Chylomicrons are converted to chylomicron remnants by the hydrolysis of their triglycerides by LPL. Chylomicron remnants are rapidly cleared from the plasma by the liver. "Remnant receptors" include the LDL receptor-related protein (LRP), LDL receptors, and perhaps other receptors. Free fatty acid (FFA) released by LPL is used by muscle tissue as an energy source or taken up and stored by adipose tissue. HL, hepatic lipase; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins.
HYPERLIPIDEMIA AND ATHEROSCLEROSIS
National Cholesterol Education Program (NCEP) Guidelines for Assessing Risk
Table 31-3 Treatment Based on LDL-C Levels (2004 Revision of NCEP Adult Treatment Panel III Guidelines)
Table 31-4 Classification of Plasma Lipid Levels (mg/dL)a
NCEP Guidelines for Treatment: Managing Patients with Dyslipidemia
Table 31-5 Risk Factors for Coronary Heart Diseasea
Table 31-6 Assessing 10-Year Risk of CVD Eventsa
Arterial Wall Biology and Plaque Stability
Table 31-7 Secondary Causes of Dyslipidemia
Whom and When to Treat?
Treatment of Type 2 Diabetes Patients
Metabolic Syndrome
Table 31-8 Clinical Identification of the Metabolic Syndrome
Treatment of Hypertriglyceridemia
Table 31-9 Guidelines Based on LDL-C and Total Cholesterol:HDL-C Ratio for Treatment of Low HDL-C Patientsa
DRUG THERAPY OF DYSLIPIDEMIA
Statins
Figure 31-2. Chemical structures of the statins and the reaction catalyzed by HMG-CoA reductase.
Table 31-10 Dose (mg) of Statins Required to Achieve Various Reductions in Low-Density-Lipoprotein Cholesterol from Baseline
Absorption, Metabolism, and Excretion
Adverse Effects and Drug Interactions
Bile-Acid Sequestrants
Figure 31-3. Structures of cholestyramine, colestipol, and colesevelam.
Niacin (Nicotinic Acid)
Fibric Acid Derivatives: PPAR Activators
Figure 31-4. Structures of the fibric acids.
Ezetimibe and the Inhibition of Dietary Cholesterol Uptake
CLINICAL SUMMARY
BIBLIOGRAPHY
Section IV Inflammation, Immunomodulation, and Hematopoiesis
chapter 32 Histamine, Bradykinin, and Their Antagonists
HISTAMINE
Distribution and Biosynthesis of Histamine
Figure 32-1. Structure of histamine and some H1, H2, H3, and H4 agonists- Dimaprit and 4-methylhistamine, originally identified as specific H2 agonists, have a much higher affinity for the H4 receptor; 4-methylhistamine is the most specific available H4 agonist, with ~10-fold higher affinity than dimaprit, a partial H4 agonist. Impromidine is among the most potent H2 agonists but also is an antagonist at H1 and H3 receptors and a partial agonist at H4 receptors. (R)-α-Methylhistamine and imetit are high-affinity agonists of H3 receptors and lower-affinity full agonists at H4 receptors.
Table 32-1 Characteristics of Histamine Receptors
Figure 32-2. Pathways of histamine synthesis and metabolism in humans. Histamine is synthesized from histidine by decarboxylation. Histamine is metabolized via two pathways, predominantly by methylation of the ring followed by oxidative deamination (left side of figure), and secondarily by oxidative deamination and then conjugation with ribose.
Release and Functions of Endogenous Histamine
Pharmacological Effects
Clinical Uses
H1 RECEPTOR ANTAGONISTS
Pharmacological Properties
Effects on Physiological Systems.
Figure 32-3. Representative H1 antagonists.
Therapeutic Uses
Table 32-2 Preparations and Dosage of Representative H1 Receptor Antagonistsa
H2 RECEPTOR ANTAGONISTS
THE HISTAMINE H3 RECEPTOR AND ITS ANTAGONISTS
THE HISTAMINE H4 RECEPTOR AND ITS ANTAGONISTS
CLINICAL SUMMARY: ANTI-HISTAMINES
BRADYKININ, KALLIDIN, AND THEIR ANTAGONISTS
Figure 32-4. Synthesis and receptor interactions of active peptides generated by the kallikrein-kinin and renin-angiotensin systems. Bradykinin is generated by the action of plasma kallikrein on high-molecular-weight (HMW) kininogen, whereas kallidin (Lys1-bradykinin) is released by the hydrolysis of low-molecular-weight (LMW) kininogen by tissue kallikrein. Kallidin and bradykinin are the natural ligands of the B2 receptor but can be converted to corresponding agonists of the B1 receptor by removal of the C-terminal Arg by kininase I-type enzymes: the plasma membrane-bound carboxypeptidase M (CPM) or soluble plasma carboxypeptidase N (CPN). Kallidin or [des-Arg10]-kallidin can be converted to the active peptides bradykinin or to [des-Arg9]-bradykinin by aminopeptidase cleavage of the N-terminal Lys residue. In a parallel fashion, the inactive decapeptide angiotensin I is generated by the action of renin on the plasma substrate angiotensinogen. By removal of the C-terminal His-Leu dipeptide, angiotensin-converting enzyme (ACE) generates the active peptide angiotensin II (AngII). These two systems have opposing effects. AngII is a potent vasoconstrictor that also causes aldosterone release and Na+ retention via activation of the AT1 receptor; bradykinin is a vasodilator that stimulates Na+ excretion by activating the B2 receptor. ACE generates active AngII and, at the same time, inactivates bradykinin and kallidin; thus, its effects are prohypertensive, and ACE inhibitors are effective antihypertensive agents. The B2 receptor mediates most of bradykinin's effects under normal circumstances, whereas synthesis of the B1 receptor is induced by inflammatory mediators in inflammatory conditions. Both B1 and B2 receptors couple through Gq to activate PLC and increase intracellular Ca2+; the physiological response depends on receptor distribution on particular cell types and occupancy by agonist peptides. For instance, on endothelial cells, activation of B2 receptors results in Ca2+-calmodulin-dependent activation of eNOS and generation of NO, which causes cyclic GMP accumulation and relaxation in neighboring smooth muscle cells. However, in endothelial cells under inflammatory conditions, B1 receptor stimulation results in prolonged NO production via Gi and MAP kinase-dependent activation of iNOS expression. On smooth muscle cells, activation of kinin receptors coupling through Gq results in an increased [Ca2+]i and contraction. B1 and B2 receptors also can couple through Gi to activate PLA2, causing the release of arachidonic acid and the local generation of prostanoids (PGs) and other metabolites such as endothelium-derived hyperpolarizing factor (EDHF). Kallikrein also plays a role in the intrinsic blood coagulation pathway (see Chapter 30).
The Endogenous Kallikrein-Kininogen-Kinin System
Table 32-3 Structure of Kinin Agonists and Antagonists
Figure 32-5. Schematic diagram of the degradation of bradykinin. Arrows denote the primary cleavage sites in bradykinin. Bradykinin and kallidin are inactivated in vivo primarily by kininase II [angiotensin-converting enzyme (ACE)]. Neutral endopeptidase 24.11 (neprilysin), cleaves bradykinin and kallidin at the same Pro-Phe bond as ACE and also is classified as a kininase II-type enzyme. In addition, aminopeptidase P can inactivate bradykinin by hydrolyzing the N-terminal Arg1-Pro2 bond, leaving bradykinin susceptible to further degradation by dipeptidyl peptidase IV. Bradykinin and kallidin are converted to their respective des-Arg9 or des-Arg10 metabolites by kininase I-type carboxypeptidases M and N. Unlike the parent peptides, these kinin metabolites are potent ligands for B1 kinin receptors but not B2 kinin receptors.
Functions and Pharmacology of Kallikreins and Kinins
Systems Pharmacology of Kinins
Kallikrein Inhibitors
CLINICAL SUMMARY: KININS
BIBLIOGRAPHY
chapter 33 Lipid-Derived Autacoids: Eicosanoids and Platelet-Activating Factor
EICOSANOIDS
Figure 33-1. Metabolism of arachidonic acid (AA). The cyclooxygenase (COX) pathway is highlighted in gray. The lipoxygenase (LOX) pathways are expanded in Figure 33-2. Major degradation pathways are shown in Figure 33-3. Cyclic endoperoxides (PGG2 and PGH2) arise from the sequential cyclooxygenase and hydroperoxidase actions of COX-1 or COX-2 on AA released from membrane phospholipids. Subsequent products are generated by tissue-specific synthases and transduce their effects via membrane-bound receptors (blue boxes). Dashed lines indicate putative ligand-receptor interactions. Epoxyeicosatrienoic acids (EETs; shaded in blue) and isoprostanes are generated via CYP activity and non-enzymatic free radical attack, respectively. COX-2 can use modified arachidonoylglycerol, an endocannabinoid, to generate the glyceryl prostaglandins. Aspirin and tNSAIDs are nonselective inhibitors of COX-1 and COX-2 but do not affect LOX activity. Epilipoxins are generated by COX-2 following its acetylation by aspirin (see Figure 33-2). Dual 5-LOX-COX inhibitors interfere with both pathways. See the text for other abbreviations.
Figure 33-2. Lipoxygenase pathways of arachidonic acid metabolism. 5-LOX-activating protein (FLAP) presents arachidonic acid to 5-LOX, leading to the generation of the LTs. CysLTs are shaded in gray. Lipoxins (shaded in orange) are products of cellular interaction via a 5-LOX-12-LOX pathway or via a 15-LOX-5-LOX pathway. Biological effects are transduced via membrane-bound receptors (blue boxes). The dashed line indicates putative ligand-receptor interactions. Zileuton inhibits 5-LOX but not the COX pathways (expanded in Figure 33-1). Dual 5-LOX-COX inhibitors interfere with both pathways. CysLT antagonists prevent activation of the CysLT1 receptor. See the text for abbreviations.
Pharmacological Properties of Eicosanoids
Figure 33-3. Major pathways of prostanoid degradation. Active metabolites are shaded in gray. Major urinary metabolites are shaded in orange. The red dashed lines indicate reactions that use common enzymatic processes. M, metabolite. See the text for other abbreviations.
Table 33-1 Eicosanoid Receptors
Figure 33-4. Prostanoid receptors and their primary signaling pathways. Prostanoid receptors are members of the heptaspanning, G protein-coupled receptor superfamily. The terms "relaxant," "contractile," and "inhibitory" refer to the phylogenetic characterization of their primary effects. **All EP3 isoforms couple through Gi, but some can also activate Gs or G12/13 pathways. See the text for additional details.
Endogenous Prostaglandins, Thromboxanes, and Leukotrienes: Functions in Physiological and Pathological Processes
Pharmacological Effects
Therapeutic Uses
PLATELET-ACTIVATING FACTOR
Figure 33-5. Synthesis and degradation of platelet-activating factor (PAF). RCOO- is a mixture of fatty acids but is enriched in arachidonic acid that may be metabolized to eicosanoids. CoA, coenzyme A.
BIBLIOGRAPHY
chapter 34 Anti-Inflammatory, Antipyretic, and Analgesic Agents; Pharmacotherapy of Gout
Inflammation, Pain, and Fever
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
Figure 34-1. Classification of NSAIDs by chemical similarity (panel A), cyclooxygenase (COX) isoform selectivity (panel B), and plasma t1/2 (panel C). The COX selectivity chart is plotted from data published in Warner et al., 1999, and FitzGerald and Patrono, 2001. tNSAIDs, traditional nonsteroidal anti-inflammatory drugs.
Mechanism of Action
Figure 34-2. Structural basis for cyclooxygenase-2 (COX-2)-selective inhibition. The active centers of COX-1 and COX-2 are shown crystallized with the nonselective inhibitor flurbiprofen (COX-1) (Picot et al., 1994) and the experimental COX-2 inhibitor SC-558 (Kurumbail et al., 1996). The active center of COX-2 is characterized by a larger side pocket, which can accommodate molecules with bulkier side chains than COX-1. (Courtesy of Dr. Vineet Sangar.)
Absorption, Distribution, and Elimination
Therapeutic Uses
Table 34-1 Classification and Comparison of Nonsteroidal Analgesics
Other Clinical Uses
Adverse Effects of NSAID Therapy
Table 34-2 Common and Shared Side Effects of NSAIDs
Drug Interactions
Pediatric and Geriatric Indications and Problems
SPECIFIC PROPERTIES OF INDIVIDUAL NSAIDS
ASPIRIN AND OTHER SALICYLATES
Mechanism of Action
Figure 34-3. Chemical structures of the salicylic acid derivatives.
Absorption, Distribution, and Elimination
Therapeutic Uses
Adverse Effects
Salicylate Intoxication
PARA-AMINOPHENOL DERIVATIVES: ACETAMINOPHEN
Mechanism of Action
Absorption, Distribution, and Elimination
Acetaminophen Intoxication
ACETIC ACID DERIVATIVES
Indomethacin
Sulindac
Etodolac
Tolmetin
Ketorolac
Nabumetone
Diclofenac
Lumiracoxib
PROPIONIC ACID DERIVATIVES
Figure 34-4. Chemical structures of propionic acid derivatives.
Ibuprofen
Naproxen
Other Propionic Acid Derivatives
THE FENAMATES
ENOLIC ACIDS (OXICAMS)
Piroxicam
Meloxicam
Other Oxicams
PYRAZOLON DERIVATIVES
DIARYL HETEROCYCLIC COX-2-SELECTIVE NSAIDS
Celecoxib
Parecoxib
Etoricoxib
Rofecoxib
OTHER NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
Apazone (Azapropazone)
Nimesulide
CLINICAL SUMMARY: NSAIDs
DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS
Table 34-3 Disease-Modifying Anti-Rheumatic Drugs
PHARMACOTHERAPY OF GOUT
Colchicine
Allopurinol
Febuxostat
Rasburicase
Uricosuric Agents
Mechanism of Action
Benzbromarone
CLINICAL SUMMARY: TREATMENT OF GOUT
BIBLIOGRAPHY
chapter 35 Immunosuppressants, Tolerogens, and Immunostimulants
THE IMMUNE RESPONSE
IMMUNOSUPPRESSION
General Approach to Organ Transplantation Therapy
Table 35-1 Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation
Adrenocortical Steroids
Calcineurin Inhibitors
Figure 35-1. Chemical structures of immunosuppressive drugs.
Cyclosporine
Figure 35-2. Mechanisms of action of cyclosporine, tacrolimus, and sirolimus on T lymphocytes. Both cyclosporine and tacrolimus bind to immunophilins (cyclophilin and FK506-binding protein [FKBP], respectively), forming a complex that binds the phosphatase calcineurin and inhibits the calcineurin-catalyzed dephosphorylation essential to permit movement of the nuclear factor of activated T cells (NFAT) into the nucleus. NFAT is required for transcription of interleukin-2 (IL-2) and other growth- and differentiationassociated cytokines (lymphokines). Sirolimus (rapamycin) works at a later stage in T-cell activation, downstream of the IL-2 receptor. Sirolimus also binds FKBP, but the FKBP-sirolimus complex binds to and inhibits the mammalian target of rapamycin (mTOR), a kinase involved in cell-cycle progression (proliferation). TCR, T-cell receptor. (From Pattison et al., 1997, with permission. Copyright © Lippincott Williams & Wilkins. http://lww.com.)
Anti-Proliferative and Antimetabolic Drugs
Sirolimus
Everolimus
Azathioprine
Mycophenolate Mofetil
Figure 35-3. Generation of monoclonal antibodies. Mice are immunized with the selected antigen, and spleen or lymph node is harvested and B cells separated. These B cells are fused to a suitable B-cell myeloma that has been selected for its inability to grow in medium supplemented with hypoxanthine, aminopterin, and thymidine (HAT). Only myelomas that fuse with B cells can survive in HAT-supplemented medium. The hybridomas expand in culture. Those of interest based on a specific screening technique are then selected and cloned by limiting dilution. Monoclonal antibodies can be used directly as supernatants or ascites fluid experimentally but are purified for clinical use. HPRT, hypoxanthine-guanine phosphoribosyl transferase. (Reproduced with permission from Krensky A.M. and Clayberger C. Transplantation immunobiology. In, Pediatric Nephrology, 5th ed. (Avner E.D., Harmon W.E., Niauder P., eds) Lippincott Williams & Wilkins, Philadelphia, 2004. (http://lww.com) .)
Biological Immunosuppression Antibodies and Fusion Receptor Protein
Antithymocyte Globulin
Monoclonal Antibodies
IL-1 Inhibition
Lymphocyte Function-Associated Antigen-1 (LFA-1) Inhibition
Alefacept
Targeting B Cells
TOLERANCE
Figure 35-4. Co-stimulation. A. Two signals are required for T-cell activation. Signal 1 is via the T-cell receptor (TCR), and signal 2 is via a co-stimulatory receptor-ligand pair. Both signals are required for T-cell activation. Signal 1 in the absence of signal 2 results in an inactivated T cell. B. One important costimulatory pathway involves CD28 on the T cell and B7-1 (CD80) and B7-2 (CD86) on the antigen-presenting cell (APC). After a T cell is activated, it expresses additional co-stimulatory molecules. CD152 is CD40 ligand, which interacts with CD40 as a co-stimulatory pair. CD154 (CTLA4) interacts with CD80 and CD86 to dampen or downregulate an immune response. Antibodies against CD80, CD86, and CD152 are being evaluated as potential therapeutic agents. CTLA4-Ig, a chimeric protein consisting of part of an immunoglobulin molecule and part of CD154, also has been tested as a therapeutic agent. (Adapted with permission from Clayberger, C., and Krensky, A.M. Mechanisms of allograft rejection. In, Immunologic Renal Diseases. (Nielson, E.G., and Couser, W.G., eds) Lippincott-Raven, Philadelphia, 2001. (http://lww.com).)
Figure 35-5. Structure of belatacept, a CLTA4Ig congener. For details, see the text and Figure 35-4.
Donor Cell Chimerism
Soluble HLA
Antigens
IMMUNOSTIMULATION
General Principles
Immunostimulants
Recombinant Cytokines
Immunization
Table 35-2 Selected Immune Globulin Preparations
A CASE STUDY: IMMUNOTHERAPY FOR MULTIPLE SCLEROSIS
Table 35-3 Pharmacotherapy of Multiple Sclerosis
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 36 Pulmonary Pharmacology
INTRODUCTION
MECHANISMS OF ASTHMA
Figure 36-1. Cellular mechanisms of asthma. Myriad inflammatory cells are recruited and activated in the airways, where they release multiple inflammatory mediators, which can also arise from structural cells. These mediators lead to bronchoconstriction, plasma exudation and edema, vasodilation, mucus hypersecretion, and activation of sensory nerves. Chronic inflammation leads to structural changes, including subepithelial fibrosis (basement membrane thickening), airway smooth muscle hypertrophy and hyperplasia, angiogenesis, and hyperplasia of mucus-secreting cells.
MECHANISMS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Figure 36-2. Cellular mechanisms in chronic obstructive pulmonary disease. Cigarette smoke and other irritants activate epithelial cells and macrophages in the lung to release mediators that attract circulating inflammatory cells, including monocytes (which differentiate to macrophages within the lung), neutrophils, and T lymphocytes (TH1 and TC1 cells). Fibrogenic factors released from epithelial cells and macrophages lead to fibrosis of small airways. Release of proteases results in alveolar wall destruction (emphysema) and mucus hypersecretion (chronic bronchitis).
ROUTES OF DRUG DELIVERY TO THE LUNGS
Inhaled Route
Figure 36-3. Schematic representation of the deposition of inhaled drugs (e.g., corticosteroids, β2 agonists). Inhalation therapy deposits drugs directly, but not exclusively, in the lungs. Distribution between lungs and oropharynx depends mostly on the particle size and the efficiency of the delivery method. Most material will be swallowed and absorbed, entering systemic circulation after undergoing the first-pass effect in the liver. Some drug will also be absorbed into the systemic circulation from the lungs. Use of a largevolume spacer will reduce the amount of drug deposited on oropharynx, thereby reducing amount swallowed and absorbed from GI tract, thus limiting systemic effects. MDI, metered-dose inhaler.
Particle Size
Pharmacokinetics
Delivery Devices
Oral Route
Parenteral Route
BRONCHODILATORS
β2 ADRENERGIC AGONISTS
Figure 36-4. Chemical structure of some adrenergic agonists showing development from catecholamines by substitutions on the catechol nucleus and side chain.
Mode of Action
Figure 36-5. Molecular actions of β2 agonists to induce relaxation of airway smooth muscle cells. Activation of β2 receptors (β2AR) results in activation of adenylyl cyclase (AC) via a stimulatory G protein (Gs), leading to an increase in intracellular cyclic AMP and activation of PKA. PKA phosphorylates a variety of target substrates, resulting in opening of Ca2+-activated K+ channels (KCa), thereby facilitating hyperpolarization, decreased phosphoinositide (PI) hydrolysis, increased Na+/Ca2+ exchange, increased Na+,Ca2+- ATPase activity, and decreased myosin light chain kinase (MLCK) activity. β2 Receptors may also couple to KCa via Gs. PDE, cyclic nucleotide phosphodiesterase.
Anti-Inflammatory Effects
Clinical Use
Table 36-1 Side Effects of β2 Agonists
Future Developments
METHYLXANTHINES
Figure 36-6. Theophylline affects multiple cell types in the airway.
Table 36-2 Factors Affecting Clearance of Theophylline
Table 36-3 Side Effects of Theophylline and Mechanisms
Summary and Future Developments
MUSCARINIC CHOLINERGIC ANTAGONISTS
Mode of Action
Figure 36-7. Anticholinergic drugs inhibit vagally mediated airway tone, thereby producing bronchodilation. This effect is small in normal airways but is greater in airways of patients with chronic obstructive pulmonary disease (COPD), which are structurally narrowed and have higher resistance to airflow because airway resistance is inversely related to the fourth power of the radius (r). ACh, acetylcholine.
NOVEL CLASSES OF BRONCHODILATORS
CORTICOSTEROIDS
Figure 36-8. Chemical structures of commonly used inhaled corticosteroids, showing changes from hydrocortisone nucleus.
Figure 36-9. Mechanism of anti-inflammatory action of corticosteroids in asthma. Inflammatory genes are activated by inflammatory stimuli (IL-1β, TNF-α, etc.), resulting in activation of IKKβ (inhibitor of I-κB kinase-β), which activates the transcription factor nuclear factor κB (NF-κB). A dimer of p50 and p65 NF-κB proteins translocates to the nucleus and binds to specific κB recognition sites and also to coactivators, such as CREB-binding protein (CBP), which have intrinsic histone acetyltransferase (HAT) activity. This results in acetylation of core histones and consequent increased expression of genes encoding multiple inflammatory proteins. Cytosolic glucocorticoid receptors (GR) bind corticosteroids; the receptor-ligand complexes translocate to the nucleus and bind to coactivators to inhibit HAT activity in two ways: directly and, more importantly, by recruiting histone deacetylase-2 (HDAC2), which reverses histone acetylation, leading to the suppression of activated inflammatory genes.
Figure 36-10. Effect of corticosteroids on inflammatory and structural cells in the airways.
Routes of Administration and Dosing
Table 36-4 Side Effects of Inhaled Corticosteroids
Cromones
MEDIATOR ANTAGONISTS
Figure 36-11. Effects of cysteinyl-leukotrienes on the airways and their inhibition by anti-leukotrienes. AS, aspirin sensitive; 5-LO, 5′-lipoxygenase; LT, leukotriene; PAF, platelet-activating factor.
IMMUNOMODULATORY THERAPIES
Immunosuppressive Therapy
Anti-IgE Receptor Therapy
Specific Immunotherapy
Figure 36-12. Immunoglobulin (Ig)E plays a central role in allergic diseases. Blocking IgE using an antibody, such as omalizumab, is a rational therapeutic approach. IgE may activate high-affinity receptors (FcɛRI) on mast cells as well as low-affinity receptors (FcɛRII, CD23) on other inflammatory cells. Omalizumab prevents these interactions and the resulting inflammation. cys-LT, cysteinylleukotriene; IL, interleukin; PG, prostaglandin.
New Drugs in Development for Asthma and Chronic Obstructive Pulmonary Disease
Protease Inhibitors
New Anti-Inflammatory Drugs
Mucoregulators
Mucolytics
Expectorants
ANTITUSSIVES
DRUGS FOR DYSPNEA AND VENTILATORY CONTROL
Drugs for Dyspnea
Ventilatory Stimulants
PHARMACOTHERAPY OF PULMONARY ARTERIAL HYPERTENSION
Endothelin Receptor Antagonists
Phosphodiesterase 5 Inhibitors
Figure 36-13. Interactions of endothelium and vascular smooth muscle in pulmonary artery hypertension (PAH). A. In normal pulmonary artery, there is a balance between constrictor and relaxant influences that may be viewed as competition between Ca2+ signaling pathways and cyclic nucleotide signaling pathways in vascular smooth muscle (VSM). Endothelin (ET-1) binds to the ETA receptor on VSM cells and activates the Gq-PLC-IP3 pathway to increase cytosolic Ca2+; ET-1 may also couple to Gi to inhibit cyclic AMP (cAMP) production. In depolarizing VSM cells, Ca2+ may enter via the L-type Ca2+ channel (Cav1.2). Endothelial cells also produce relaxant factors, prostacyclin (PGI2) and NO. NO stimulates the soluble guanylyl cyclase (cGC), causing accumulation of cyclic GMP (cGMP) in VSM cells; PGI2 binds to the IP prostanoid receptor and stimulates the Gs-adenylyl cyclase pathway to enhance cAMP accumulation; elevation of these cyclic nucleotides promotes VSM relaxation (see Chapter 3). B. In PAH, ET-1 production is enhanced, production of PGI2 and NO is reduced, and the balance is shifted toward constriction and proliferation of vascular smooth muscle. C. In treating PAH, ETA receptor antagonists can reduce the constrictor effects of ET-1, and Ca2+ channel antagonists can further reduce Ca2+-dependent contraction. Exogenous PGI2 and NO can be supplied to promote vasodilation (relaxation of VSM); inhibition of PDE5 can enhance the relaxant effect of NO by inhibiting the degradation of cGMP, thereby promoting intracellular accumulation of cGMP and relaxation of VSM. Thus, these drugs can reduce Ca2+ signaling and enhance cyclic nucleotide signaling, restoring the balance between the forces of contraction/proliferation and relaxation/anti-proliferation. Remodeling and deposition of extracellular matrix by adjacent fibroblasts is influenced positively and negatively by the same contractile and relaxant signaling pathways, respectively.
BIBLIOGRAPHY
chapter 37 Hematopoietic Agents: Growth Factors, Minerals, and Vitamins
Hematopoietic Growth Factors
ERYTHROPOIESIS STIMULATING AGENTS
Figure 37-1. Sites of action of hematopoietic growth factors in the differentiation and maturation of marrow cell lines. A self-sustaining pool of marrow stem cells differentiates under the influence of specific hematopoietic growth factors to form a variety of hematopoietic and lymphopoietic cells. Stem cell factor (SCF), ligand (FL), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF), together with cell-cell interactions in the marrow, stimulate stem cells to form a series of burst-forming units (BFU) and colony-forming units (CFU): CFU-GEMM (granulocyte, erythrocyte, monocyte and megakaryocyte), CFU-GM (granulocyte and macrophage), CFU-Meg (megakaryocyte), BFU-E (erythrocyte), and CFU-E (erythrocyte). After considerable proliferation, further differentiation is stimulated by synergistic interactions with growth factors for each of the major cell lines—granulocyte colony-stimulating factor (G-CSF), monocyte/macrophage-stimulating factor (M-CSF), thrombopoietin, and erythropoietin. Each of these factors also influences the proliferation, maturation, and in some cases the function of the derivative cell line (Table 37-1).
Table 37-1 Hematopoietic Growth Factors
MYELOID GROWTH FACTORS
Figure 37-2. Cytokine-cell interactions. Macrophages, T cells, B cells, and marrow stem cells interact via several cytokines (IL-1, IL-2, IL-3, IL-4, IFN [interferon]-γ, GM-CSF, and G-CSF) in response to a bacterial or a foreign antigen challenge. See Table 37-1 for the functional activities of these various cytokines.
Thrombopoietic Growth Factors
Drugs Effective in Iron Deficiency and Other Hypochromic Anemias
IRON AND IRON SALTS
Table 37-2 The Body Content of Iron
Figure 37-3. Pathways of iron metabolism in humans (excretion omitted).
Table 37-3 Iron Requirements for Pregnancy
Table 37-4 Daily Iron Intake and Absorption
Figure 37-4. Effect of iron status on the absorption of nonheme iron in food. The percentages of iron absorbed from diets of low, medium, and high bioavailability in individuals with iron stores of 0, 250, 500, and 1000 mg are portrayed. (After Monsen et al., 1978; reproduced with permission by the American Journal of Clinical Nutrition. © Am J Clin Nutr. American Society for Clinical Nutrition.)
Figure 37-5. Sequential changes (from left to right) in the development of iron deficiency in the adult. Red rectangles indicate abnormal test results. RE marrow Fe, reticuloendothelial hemosiderin; RBC, red blood cells. (Adapted from Hillman RS and Finch CA. Red Cell Manual, 7th ed. FA Davis Co., Philadelphia, 1997. Used with permission.)
Treatment of Iron Deficiency
Table 37-5 Average Response to Oral Iron
Copper
Pyridoxine
Riboflavin
B12, Folic Acid, and the Treatment of Megaloblastic Anemias
Figure 37-6. Interrelationships and metabolic roles of vitamin B12 and folic acid. See text for explanation and Figure 37-7 for structures of the various folate coenzymes. FIGLU, formiminoglutamic acid, which arises from the catabolism of histidine; TcII, transcobalamin II; CH3H4PteGlu1, methyltetrahydrofolate.
Vitamin B12
Figure 37-7. The structures and nomenclature of vitamin B12 congeners.
Figure 37-8. The absorption and distribution of vitamin B12. Deficiency of vitamin B12 can result from a congenital or acquired defect in any one of the following: (1) inadequate dietary supply; (2) inadequate secretion of intrinsic factor (classical pernicious anemia); (3) ileal disease; (4) congenital absence of transcobalamin II (TcII); or (5) rapid depletion of hepatic stores by interference with reabsorption of vitamin B12 excreted in bile. The utility of measurements of the concentration of vitamin B12 in plasma to estimate supply available to tissues can be compromised by liver disease and (6) the appearance of abnormal amounts of transcobalamins I and III (TcI and III) in plasma. Finally, the formation of methylcobalamin requires (7) normal transport into cells and an adequate supply of folic acid as CH3H4PteGlu1.
Folic Acid
Figure 37-9. The structures and nomenclature of pteroylglutamic acid (folic acid) and its congeners. X represents additional residues of glutamate; polyglutamates are the storage and active forms of the vitamin. The subscript that designates the number of residues of glutamate is frequently omitted because this number is variable.
Figure 37-10. Absorption and distribution of folate derivatives. Dietary sources of folate polyglutamates are hydrolyzed to the monoglutamate, reduced, and methylated to CH3H4PteGlu1 during gastrointestinal transport. Folate deficiency commonly results from (1) inadequate dietary supply and (2) small intestinal disease. In patients with uremia, alcoholism, or hepatic disease there may be defects in (3) the concentration of folate binding proteins in plasma and (4) the flow of CH3H4PteGlu1 into bile for reabsorption and transport to tissue (the folate enterohepatic cycle). Finally, vitamin B12 deficiency will (5) "trap" folate as CH3H4PteGlu, thereby reducing the availability of H4PteGlu1 for its essential roles in purine and pyrimidine synthesis.
CLINICAL SUMMARY
BIBLIOGRAPHY
Section V Hormones and Hormone Antagonists
chapter 38 Introduction To Endocrinology: The Hypothalamic-Pituitary Axis
ENDOCRINOLOGY AND HORMONES: GENERAL CONCEPTS
DISORDERS OF ENDOCRINE REGULATION
THE HYPOTHALAMIC-PITUITARY-ENDOCRINE AXIS
Table 38-1 Hormones that Integrate the Hypothalamic-Pituitary-Endocrine Axis
Figure 38-1. Organization of the anterior and posterior pituitary gland. Hypothalamic neurons in the supraoptic (SON) and paraventricular (PVN) nuclei synthesize arginine vasopressin (AVP) or oxytocin (OXY). Most of their axons project directly to the posterior pituitary, from which AVP and OXY are secreted into the systemic circulation to regulate their target tissues. Neurons that regulate the anterior lobe cluster in the mediobasal hypothalamus, including the PVH and the arcuate (ARC) nuclei. They secrete hypothalamic releasing hormones, which reach the anterior pituitary via the hypothalamic-adenohypophyseal portal system and stimulate distinct populations of pituitary cells. These cells, in turn, secrete the trophic (signal) hormones, which regulate endocrine organs and other tissues. See Table 38-1 for abbreviations.
PITUITARY HORMONES AND THEIR HYPOTHALAMIC RELEASING FACTORS
Table 38-2 Properties of the Protein Hormones of the Human Adenohypophysis and Placenta
SOMATOTROPIC HORMONES: GROWTH HORMONE AND PROLACTIN
Physiology of the Somatotropic Hormones
Figure 38-2. Growth hormone secretion and actions. Two hypothalamic factors, growth hormone-releasing hormone (GHRH) and somatostatin (SST) stimulate or inhibit the release of growth hormone (GH) from the pituitary, respectively. Insulin-like growth factor-1 (IGF-1), a product of GH action on peripheral tissues, causes negative feedback inhibition of GH release by acting at the hypothalamus and the pituitary. The actions of GH can be direct or indirect (mediated by IGF-1). See text for discussion of the other agents that modulate GH secretion and of the effects of locally produced IGF-1. Inhibition, −; stimulation, +.
Figure 38-3. Structures of somatostatin-14 and selected synthetic analogs. The amino acid sequence of somatostatin (SST)-14 is shown. Residues that play key roles in receptor binding, as discussed in the text, are shown in red. Also shown are the structures of the two clinically available synthetic analogs of somatostatin, octreotide and lanreotide, and three other analogs that have been used in clinical trials, seglitide, vapreotide, and pasireotide. APro, [(2-aminoethyl) aminocarboxyl oxy]-Lproline; D-Nal, (3-(2-napthyl)-D-alanyl; PGly, phenylglycine; BTyr, benzyltyrosine.
Figure 38-4. Prolactin secretion and actions. Prolactin is the only anterior pituitary hormone for which a unique stimulatory releasing factor has not been identified. Thyrotropin-releasing hormone (TRH), however, can stimulate prolactin release and dopamine can inhibit it. Suckling induces prolactin secretion, and prolactin affects lactation and reproductive functions but also has varied effects on many other tissues. Prolactin is not under feedback control by peripheral hormones.
Figure 38-5. Mechanisms of growth hormone and prolactin action and of GH receptor antagonism. Left (A): The binding of GH to a homodimer of the growth hormone receptor (GHR) induces autophosphorylation of JAK2. JAK2 then phosphorylates cytoplasmic proteins that activate downstream signaling pathways, including STAT5 and mediators upstream of MAPK, which ultimately modulate gene expression. The structurally related prolactin receptor also is a ligand activated homodimer that recruits the JAK-STAT signaling pathway (see text for further details). The GHR also activates IRS-1, which may mediate the increased expression of glucose transporters on the plasma membrane. The diagram does not reflect the localization of the intracellular molecules, which presumably exist in multicomponent signaling complexes. JAK2, janus kinase 2; IRS-1, insulin receptor substrate-1; PI3K, phosphatidyl inositol-3 kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; SHC, Src homology containing. Right (B): Pegvisomant, a recombinant pegylated variant of human GH, contains amino acid substitutions that increase the affinity for one site of the GHR but do not activate its downstream signaling cascade. It thus interferes with GH signaling in target tissues.
Pathophysiology of the Somatotropic Hormones
Pharmacotherapy of Disorders of the Somatotropin Hormones
Therapeutic Uses
Dopamine Receptor Agonists
Figure 38-6. Dopamine receptor agonists used in the treatment of prolactinomas. The structures of dopamine, the predominant regulator of prolactin secretion, and of dopaminergic agonists that are used to inhibit prolactin secretion are shown. Bromocriptine and cabergoline are ergot derivatives, whereas quinagolide is not. The β-phenylethylamine region of structural similarity between dopamine and the agonists is shown in red.
Therapy of Growth Hormone Deficiency
Insulin-like Growth Factor 1 (IGF-1)
THE GYCOPROTEIN HORMONES: TSH AND THE GONADOTROPINS
Figure 38-7. The hypothalamic-pituitary-gonadal axis. A single hypothalamic releasing factor, gonadotropin-releasing hormone (GnRH), controls the synthesis and release of both gonadotropins (LH and FSH) in males and females. Gonadal steroid hormones (androgens, estrogens, and progesterone) exert feedback inhibition at the level of the pituitary and the hypothalamus. The preovulatory surge of estrogen also can exert a stimulatory effect at the level of the pituitary and the hypothalamus. Inhibins, a family of polypeptide hormones produced by the gonads, specifically inhibit FSH secretion by the pituitary.
Physiology of the Gonadotropins
Table 38-3 Structures of Gonadotropin-Releasing Hormone (GnRH) and GnRH Analogs
CLINICAL DISORDERS OF THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS
Clinical Uses of GnRH and Its Synthetic Analogs
Specific Drug Formulations and Approved Indications
NATURAL AND RECOMBINANT GONADOTROPINS
Preparations
Diagnostic Uses of Gonadotropins
Therapeutic Uses of the Gonadotropins
POSTERIOR PITUITARY HORMONES: OXYTOCIN AND VASOPRESSIN
Physiology of Oxytocin
Effects of Oxytocin
Clinical Therapeutics of Oxytocin
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 39 Thyroid and Anti-Thyroid Drugs
THYROID
Figure 39-1. Thyronine, thyroid hormones, and precursors.
Figure 39-2. Structural formula of 3, 5-diiodothyronine, drawn to show the conformation in which the planes of the aromatic rings are perpendicular to each other. (Adapted from Jorgensen, 1964.)
Figure 39-3. Major pathways of thyroid hormone biosynthesis and release. Abbreviations: Tg, thyroglobulin; DIT, diiodotyrosine; MIT, monoiodotyrosine; TPO, thyroid peroxidase; HOI, hypoiodous acid; EOI, enzyme-linked species; D1 and D2, deiodinases (see Table 39-1); PTU, propylthiouracil; MMI, methimazole.
Figure 39-4. Pathways of iodothyronine deiodination.
Table 39-1 Properties of Iodothyronine Deiodinases
Figure 39-5. Deiodinase isozymes. D1, type I iodothyronine 5′-deiodinase; D2, type II iodothyronine 5′-deiodinase; D3, type III iodothyronine 5-deiodinase; BAT, brown adipose tissue.
Table 39-2 Factors that Alter Binding of Thyroxine to Thyroxine-Binding Globulin
Figure 39-6. Pathways of metabolism of thyroxine (T4) and triiodothyronine (T3). DIT, diiodotyrosine; MIT, monoiodotyrosine; T4S, T4 sulfate; T4G, T4 glucuronide; T3S, T3 sulfate; T3G, T3 glucuronide; T4K, T4 pyruvic acid; T3K, T3 pyruvic acid; Tetrac, tetraiodothyroacetic acid; Triac, triiodothyroacetic acid.
Table 39-3 Factors Influencing Oral Levothyroxine Therapy
Figure 39-7. Regulation of thyroid hormone secretion. Myriad neural inputs influence hypothalamic secretion of thyrotropinreleasing hormone (TRH). TRH stimulates release of thyrotropin (TSH, thyroid-stimulating hormone) from the anterior pituitary; TSH stimulates the synthesis and release of the thyroid hormones T3 and T4. T3 and T4 feed back to inhibit the synthesis and release of TRH and TSH. Somatostatin (SST) can inhibit TRH action, as can dopamine and high concentrations of glucocorticoids. Low levels of I- are required for thyroxine synthesis, but high levels inhibit thyroxin synthesis and release.
Figure 39-8. Thyroid hormone receptor isoforms. The percent amino acid identities of the amino terminal, DNA binding, and ligand binding domains relative to TRβ1 are shown. TRβ1 is 461 amino acids in length. TRα2 does not bind T3 or any other known ligand.
Actions of Thyroid Hormones
MAJOR CLINICAL EFFECTS OF THYROID HORMONES
Therapeutic Uses of Thyroid Hormone
Novel Thyroid Hormone Analogs and Their Potential Therapeutic Applications
ANTI-THYROID DRUGS AND OTHER THYROID INHIBITORS
Table 39-4 Anti-thyroid Compounds
Anti-Thyroid Drugs
Figure 39-9. Anti-thyroid drugs of the thiamide type.
Table 39-5 Selected Pharmacokinetic Features of Anti-thyroid Drugs
Ionic Inhibitors
Iodide
Table 39-6 Commonly Used Iodine-Containing Drugs
Radioactive Iodine
Chemotherapy in Thyroid Cancer
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 40 Estrogens and Progestins
ESTROGENS
Table 40-1 Structural Formulas of selected Estrogens
Figure 40-1. The biosynthetic pathway for the estrogens.
Physiological and Pharmacological Actions
Figure 40-2. Neuroendocrine control of gonadotropin secretion in females. The hypothalamic pulse generator located in the arcuate nucleus of the hypothalamus functions as a neuronal "clock" that fires at regular hourly intervals (A). This results in the periodic release of gonadotropin-releasing hormone (GnRH) from GnRH-containing neurons into the hypothalamic-pituitary portal vasculature (B). GnRH neurons (B) receive inhibitory input from opioid, dopamine, and GABA neurons and stimulatory input from noradrenergic neurons (NE, norepinephrine). The pulses of GnRH trigger the intermittent release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary gonadotropes (C), resulting in the pulsatile plasma profile (D). FSH and LH regulate ovarian production of estrogen and progesterone, which exert feedback controls (E). (See text and Figure 40-3 for additional details)
Figure 40-3. Hormonal relationships of the human menstrual cycle. A.Average daily values of LH, FSH, estradiol (E2), and progesterone in plasma samples from women exhibiting normal 28-day menstrual cycles. Changes in the ovarian follicle (top) and endometrium (bottom) also are illustrated schematically. Frequent plasma sampling reveals pulsatile patterns of gonadotropin release. Characteristic profiles are illustrated schematically for the follicular phase (day 9, inset on left) and luteal phase (day 17, inset on right). Both the frequency (number of pulses per hour) and amplitude (extent of change of hormone release) of pulses vary throughout the cycle. (Redrawn with permission from Thorneycroft et al., 1971. Copyright © Elsevier). B. Major regulatory effects of ovarian steroids on hypothalamic-pituitary function. Estrogen decreases the amount of folliclestimulating hormone (FSH) and luteinizing hormone (LH) released (i.e., gonadotropin pulse amplitude) during most of the cycle and triggers a surge of LH release only at mid-cycle. Progesterone decreases the frequency of GnRH release from the hypothalamus and thus decreases the frequency of plasma gonadotropin pulses. Progesterone also increases the amount of LH released (i.e., the pulse amplitude) during the luteal phase of the cycle.
Estrogen Receptors
Mechanism of Action
Figure 40-4. Molecular mechanism of action of nuclear estrogen receptor. A. Unliganded estrogen receptor (ER) exists as a monomer within the nucleus. B. Agonists such as 17β-estradiol ( ) bind to the ER and cause a ligand-directed change in conformation that facilitates dimerization and interaction with specific estrogen response element (ERE) sequences in DNA. The ER-DNA complex recruits co-activators such as SWI/SNF that modify chromatin structure, and co-activators such as steroid-receptor co-activator-1 (SRC-1) that has histone acetyltransferase (HAT) activity that further alters chromatin structure. This remodeling facilitates the exchange of the recruited proteins such that other co-activators (e.g., p300 and the TRAP complex) associate on the target gene promoter and proteins that comprise the general transcription apparatus (GTA) are recruited, with subsequent synthesis of mRNA. C. Antagonists such as tamoxifen (T) also bind to the ER but produce a different receptor conformation. The antagonist-induced conformation also facilitates dimerization and interaction with DNA, but a different set of proteins called co-repressors, such as nuclear-hormone receptor corepressor (NcoR), are recruited to the complex. NcoR further recruits proteins such as histone deacetylase I (HDAC1) that act on histone proteins to stabilize nucleosome structure and prevent interaction with the GTA.
Absorption, Fate, and Elimination
Untoward Responses
Therapeutic Uses
SELECTIVE ESTROGEN RECEPTOR MODULATORS AND ANTI-ESTROGENS
Pharmacological Effects
Absorption, Fate, and Excretion
Therapeutic Uses
Estrogen-Synthesis Inhibitors
PROGESTINS
Figure 40-5. Structural features of various progestins.
PHYSIOLOGICAL AND PHARMACOLOGICAL ACTIONS
Mechanism of Action
Absorption, Fate, and Excretion
Therapeutic Uses
ANTI-PROGESTINS AND PROGESTERONE-RECEPTOR MODULATORS
Mifepristone
Ulipristal
HORMONAL CONTRACEPTIVES
Types of Hormonal Contraceptives
Mechanism of Action
Untoward Effects
Contraindications
Choice of Contraceptive Preparations
Noncontraceptive Health Benefits
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 41 Androgens
TESTOSTERONE AND OTHER ANDROGENS
Figure 41-1. Pathway of synthesis of testosterone in the Leydig cells of the testes. In Leydig cells, the 11 and 21 hydroxylases (present in adrenal cortex) are absent but CYP17 (17 α-hydroxylase) is present. Thus androgens and estrogens are synthesized; corticosterone and cortisol are not formed. Bold arrows indicate favored pathways.
Figure 41-2. Schematic representation of the serum testosterone concentration from early gestation to old age.
Figure 41-3. Metabolism of testosterone to its major active and inactive metabolites.
Physiological and Pharmacological Effects of Androgens
Figure 41-4. Direct effects of testosterone and effects mediated indirectly via dihydrotestosterone or estradiol.
Figure 41-5. Structure of the androgen receptor.
Effects of Androgens at Different Stages of Life.
Consequences of Androgen Deficiency
Therapeutic Androgen Preparations
Attempts to Design Selective Androgens
Figure 41-6. Structures of androgens available for therapeutic use.
Figure 41-7. Pharmacokinetic profiles of three testosterone preparations during their chronic administration to hypogonadal men. Doses of each were given at time 0. Shaded areas indicate range of normal levels. [Data adapted from A. Snyder and Lawrence (1980); B. Dobs et al. (1999); C. Swerdloff et al. (2000)]
Therapeutic Uses of Androgens
ANTI-ANDROGENS
Inhibitors of Androgen Action
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 42 ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex
ADRENOCORTICOTROPIC HORMONE (ACTH; CORTICOTROPIN)
Figure 42-1. Processing of pro-opiomelanocortin to adrenocorticotropic hormone and the sequence of adrenocorticotropic hormone. The pathway by which pro-opiomelanocortin (POMC) is converted to adrenocorticotropic hormone (ACTH) and other peptides in the anterior pituitary is depicted. The amino acid sequence of human ACTH is shown. The light blue boxes behind the ACTH structure indicate regions identified as important for steroidogenic activity (residues 6–10) and binding to the ACTH receptor (15–18). α-Melanocyte-stimulating hormone also derives from the POMC precursor and contains the first 13 residues of ACTH. LPH, lipotropin; MSH, melanocyte-stimulating hormone.
Figure 42-2. The adrenal cortex contains three anatomically and functionally distinct compartments. The major functional compartments of the adrenal cortex are shown, along with the steroidogenic enzymes that determine the unique profiles of corticosteroid products. Also shown are the predominant physiological regulators of steroid production: angiotensin II (Ang II) and K+ for the zona glomerulosa and ACTH for the zona fasciculata. The physiological regulator(s) of dehydroepiandrosterone (DHEA) production by the zona reticularis are not known, although ACTH acutely increases DHEA biosynthesis.
Figure 42-3. Pathways of corticosteroid biosynthesis. The steroidogenic pathways used in the biosynthesis of the corticosteroids are shown, along with the structures of the intermediates and products. The pathways unique to the zona glomerulosa are shown in orange box, whereas those that occur in the inner zona fasciculata and zona reticularis are shown in gray box. The zona reticularis does not express 3β-HSD and thus preferentially synthesizes DHEA. CYP11A1, cholesterol side-chain cleavage enzyme; 3β-HSD, 3β-hydroxysteroid dehydrogenase; CYP17, steroid 17α-hydroxylase; CYP21, steroid 21-hydroxylase; CYP11B2, aldosterone synthase; CYP11B1, steroid 11β-hydroxylase.
Regulation of ACTH Secretion.
Figure 42-4. Overview of the hypothalamic-pituitary-adrenal (HPA) axis and the immune inflammatory network. Also shown are inputs from higher neuronal centers that regulate CRH secretion. + indicates a positive regulator, − indicates a negative regulator, + and − indicates a mixed effect, as for NE (norepinephrine). In addition, arginine vasopressin stimulates release of ACTH from corticotropes.
ADRENOCORTICAL STEROIDS
Table 42-1 Normal Daily Production Rates and Circulating Levels of the Predominant Corticosteroids
Physiological Functions and Pharmacological Effects
Table 42-2 Relative Potencies and Equivalent Doses of Representative Corticosteroids
Figure 42-5. Intracellular mechanism of action of the glucocorticoid receptor. The figure shows the molecular pathway by which cortisol (labeled S) enters cells and interacts with the glucocorticoid receptor (GR) to change GR conformation (indicated by the change in shape of the GR), induce GR nuclear translocation, and activate transcription of target genes. The example shown is one in which glucocorticoids activate expression of target genes; the expression of certain genes, including proopiomelanocortin (POMC) expression by corticotropes, is inhibited by glucocorticoid treatment. CBG, corticosteroid-binding globulin; GR, glucocorticoid receptor; S, steroid hormone; HSP90, the 90-kd heat-shock protein; HSP70, the 70-kd heatshock protein; IP, the 56-kd immunophilin; GRE, glucocorticoidresponse elements in the DNA that are bound by GR, thus providing specificity to induction of gene transcription by glucocorticoids. Within the gene are introns (gray) and exons (red); transcription and mRNA processing leads to splicing and removal of introns and assembly of exons into mRNA.
Figure 42-6. Receptor-independent mechanism by which 11 β-hydroxysteroid dehydrogenase confers specificity of corticosteroid action. Type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2) converts cortisol, which binds to both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), to cortisone, which binds to neither MR nor GR, thereby protecting the MR from the high circulating concentrations of cortisol. This inactivation allows specific responses to aldosterone in sites such as the distal nephron. The type 1 isozyme of 11β-HSD (11β-HSD1) catalyzes the reverse reaction, which converts inactive cortisone to active cortisol in such tissues as liver and fat. Only ring C of the corticosteroid is depicted; see Figure 42-7 for complete structure.
Figure 42-7. Structure and nomenclature of corticosteroid products and selected synthetic derivatives. The structure of hydrocortisone is represented in two dimensions. Note that the steroid ring system is not completely planar and the orientation of the groups attached to the steroid rings is an important determinant of the biological activity. The methyl groups at C18 and C19 and the hydroxyl group at C11 project upward (forward in the two-dimensional representation and shown by a solid line connecting the atoms) and are designated β. The hydroxyl at C17 projects below the plane (behind in the two-dimensional representation, and represented by the dashed line connecting the atoms) and is designated α.
Table 42-3 Effects of Glucocorticoids on Components of Inflammatory/Immune Responses
Absorption, Transport, Metabolism, and Excretion
Structure-Activity Relationships
Toxicity of Adrenocortical Steroids
Table 42-4 Available Preparations of Adrenocortical Steroids and Their Synthetic Analogs
Therapeutic Uses
Diagnostic Applications of Adrenocortical Steroids
INHIBITORS OF THE BIOSYNTHESIS AND ACTION OF ADRENOCORTICAL STEROIDS
ANTIGLUCOCORTICOIDS
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 43 Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia
PHYSIOLOGY OF GLUCOSE HOMEOSTASIS
Figure 43-1. Insulin, glucagon, and glucose homeostasis. A. Fasting State-In healthy humans plasma glucose is maintained in a range from 4.4–5 mM, and fatty acids near 400 µM. In the absence of nutrient absorption from the GI tract, glucose is supplied primarily from the liver and fatty acids from adipose tissue. With fasting, plasma insulin levels are low, and plasma glucagon is elevated, contributing to increased hepatic glycogenolysis and gluconeogenesis; low insulin also releases adipocytes from inhibition, permitting increased lipogenesis. Most tissues oxidize primarily fatty acids during fasting, sparing glucose for use by the CNS. B. Prandial State-During feeding, nutrient absorption causes an increases in plasma glucose, resulting in release of incretins from the gut and neural stimuli that promote insulin secretion. Under the control of insulin, the liver, sekletal muscle and adipose tissue actively take up glucose. Hepatic glucose production and lipolysis are inhibited, and total body glucose oxidation increases. The brain senses plasma glucose concentrations and provides regulatory inputs contributing to fuel homeostasis. The boldness of the arrows reflects relative intensity of action; a dashed line indicates little or no activity.
Figure 43-2. Synthesis and processing of insulin. The initial peptide, preproinsulin (110 amino acids) consists of a signal peptide (SP), B chain, C peptide, and A chain. The SP is cleaved and SS bonds form as the proinsulin folds. Two prohormone convertases, PC1 and PC2, cleave proinsulin into insulin, C peptide, and two dipeptides. Insulin and C peptide are stored in granules and co-secreted in equimolar quantities.
Figure 43-3. Regulation of insulin secretion from a pancreatic β cell. The pancreatic β cell in a resting state (fasting blood glucose) is hyperpolarized. Glucose, entering via GLUT transporters (primarily GLUT1 in humans, GLUT2 in rodents), is metabolized and elevates cellular ATP, which inhibits. K+ entry through the KATP channel; the decreased K+ conductance results in depolarization, leading to Ca2+- dependent exocytosis of stored insulin. The KATP channel, actually a hetero-octamer composed of SUR1 and Kir 6.2 subunits, is the site of action of several classes of drugs: ATP binds to and inhibits Kir 6.2; sulfonylureas and meglitinides bind to and inhibit SUR1; all 3 agents thereby promote insulin secretion. Diazoxide and ADP-Mg2+ (low ATP) bind to and activate SUR1, thereby inhibiting insulin secretion. Incretins enhance insulin secretion.
Figure 43-4. Pathways of insulin signaling. The binding of insulin to its plasma membrane receptor activates a cascade of downstream signaling events. Insulin binding activates the intrinsic tyrosine kinase activity of the receptor dimer, resulting in the tyrosine phosphorylation (Y-P) of the receptor's β subunits and a small number of specific substrates (yellow shapes): the Insulin Receptor Substrate (IRS) proteins, Gab-1 and SHC; within the membrane, a caveolar pool of insulin receptor phosphorylates caveolin (Cav), APS, and Cbl. These tyrosine-phosphorylated proteins interact with signaling cascades via SH2 and SH3 domains to mediate the effects of insulin, with specific effects resulting from each pathway. In target tissues such as skeletal muscle and adipocytes, a key event is the translocation of the Glut4 glucose transporter from intracellular vesicles to the plasma membrane; this translocation is stimulated by both the caveolar and non-caveolar pathways. In the non-caveolar pathway, the activation of PI3K is crucial, and PKB/Akt (anchored at the membrane by PIP3) and/or an atypical form of PKC is involved. In the caveolar pathway, caveolar protein flotillin localizes the signaling complex to the caveola; the signaling pathway involves series of SH2 domain interactions that add the adaptor protein CrkII, the guanine nucleotide exchange protein C3G, and small GTP-binding protein, TC10. The pathways are inactivated by specific phosphoprotein phosphatases (eg, PTB1B). In addition to the actions shown, insulin also stimulates the plasma membrane Na+,K+-ATPase by a mechanism that is still being elucidated; the result is an increase in pump activity and a net accumulation of K+ in the cell. Abbreviations: APS, adaptor protein with PH and SH2 domains; CAP, Cbl associated protein; CrkII, chicken tumor virus regulator of kinase II; GLUT4, glucose transporter 4; Gab-1, Grb-2 associated binder; MAP kinase, mitogen-activated protein kinase; PDK, phosphoinositide-dependent kinase; PI3 kinase, phosphatidylinositol-3-kinase; PIP3, phosphatidylinositol trisphosphate; PKB, protein kinase B (also called Akt); aPKC, atypical isoform of protein kinase C; Y, tyrosine residue; Y-P, phosphorylated tyrosine residue.
PATHOPHYSIOLOGY AND DIAGNOSIS OF DIABETES MELLITUS
Glucose Homeostasis and the Diagnosis of Diabetes
Table 43-1 Criteria for the Diagnosis of Diabetes
Table 43-2 Different Forms of Diabetes Mellitus
Figure 43-5. Pathophysiology of type 2 diabetes mellitus. Graphs show data from diabetic () and non-diabetic () patients, comparing postprandial insulin and glucagon secretion and hepatic glucose production, and the sensitivities of muscle glucose use and adipocyte lipolysis to insulin.
Table 43-3 Some Drugs that may Promote Hyperglycemia or Hypoglycemia
Therapy of Diabetes
Figure 43-6. Components of comprehensive diabetes care.
Insulin Therapy
Table 43-4 Goals of Therapy in Diabetes
Table 43-5 Properties of Insulin Preparations
Figure 43-7. Insulin analogs. Modifications of native insulin can alter its pharmacokinetic profile. Reversing amino acids 28 and 29 in the B chain (lispro) or substituting Asp for Pro28B (aspart) gives analogs with reduced tendencies for molecular self-association that are faster acting. Altering Asp3B to Lys and Lys29B to Glu produces an insulin (glulisine) with a more rapid onset and a shorter duration of action. Substituting Gly for Asn21A and lengthening the B chain by adding Arg31 and Arg32 produces a derivative (glargine) with reduced solubility at pH 7.4 that is, consequently, absorbed more slowly and acts over a longer period of time. Deleting Thr30B and adding a myristoyl group to the ɛ-amino group of Lys29B (detemir) enhances reversible binding to albumin, thereby slowing transport across vascular endothelium to tissues and providing prolonged action.
Figure 43-8. Commonly used insulin regimens. Panel A shows administration of a long-acting insulin like glargine (detemir could also be used but often requires twice-daily administration) to provide basal insulin and a pre-meal short-acting insulin analog (Table 43-5). Panel B shows a less intensive insulin regimen with BID injection of NPH insulin providing basal insulin and regular insulin or an insulin analog providing meal-time insulin coverage. Only one type of shorting-acting insulin would be used. Panel C shows the insulin level attained following subcutaneous insulin (short-acting insulin analog) by an insulin pump programmed to deliver different basal rates. At each meal, an insulin bolus is delivered. B
INSULIN SECRETAGOGUES AND ORAL HYPOGLYCEMIC AGENTS
KATP Channel Modulators:Sulfonylureas
Table 43-6 Properties of Insulin Secretagogues
Table 43-7 Structural Formulas of the Sulfonylureas
KATP Channel Modulators: Non-Sulfonylureas
AMPK and PPAR γ activators
Metformin
Table 43-8 Comparison of Metformin and Thiazolidinediones
Thiazolidinediones
GLP-1-Based Agents
Figure 43-9. Processing of proglucagon to glucagon, GLP1. GLP-2, and GRPP. Proglucagon is synthesized in islet α cells, intestinal enteroendocrine cells (L cells) and a subset of neurons in the hindbrain. In α cells, prohormone processing is primarily by proconvertase 2, releasing glucagon, glicentin-related pancreatic polypeptide (GRPP), and a major proglucagon fragment, containing the two glucagon-like peptides (GLPs). In L cells and neurons, proglucagon cleavage is mostly through proconvertase 1/3, giving the larger C-terminal peptides, glicentin and oxyntomodulin, and the smaller GLP-1 and GLP-2. STN, solitary tract nucleus.
Figure 43-10. Pharmacological effects of DDP-4 inhibition. DPP-4, an ectoenzyme located on the luminal side of capillary endothelial cells metabolizes the incretins, glucagon-like peptide 1 (GLP-1). and glucose-dependent insulinotropic polypeptide (GIP), by removing the two N-terminal amino acids. The target for DPP-4 cleavage is a proline or alanine residue in the second position of the primary peptide sequence. The truncated metabolites GLP-1[9–36] and GIP[3–42] are the major forms of the incretins in plasma and are inactive as insulin secretagogues. Treatment with a DPP-4 inhibitor increases the concentrations of intact GLP-1 and GIP.
DPP-4 Inhibitors
OTHER HYPOGLYCEMIC AGENTS
Alpha Glucosidase Inhibitors
Pramlintide
Bile Acid Binding Resins
Miscellaneous Agents.
COMBINED PHARMACOLOGICAL APPROACHES TO TYPE 2 DIABETES
Progressive Management of Type 2 Diabetes
Emerging Therapies for Diabetes
Figure 43-11. Treatment algorithm for management of type 2 diabetes mellitus. Patients diagnosed with type 2 diabetes, either by fasting glucose, oral glucose tolerance testing, or A1C, should have diabetes education that includes instruction on medical nutrition therapy and physical activity. Most patients newly diagnosed with type 2 diabetes have had subclinical or undiagnosed diabetes for many years previously and should be evaluated for diabetic complications (retinal exam, test for excess protein or albumin excretion in the urine, and clinical evaluation for peripheral neuropathy and vascular insufficiency); common comorbidities (hypertension and dyslipidemia) should be treated. Metformin is the consensus first line of therapy and should be started at the time of diagnosis. Failure to reach the glycemic target, generally a A1C ≤7% within 3–4 months, should prompt the addition of a second oral agent. Reinforce lifestyle interventions at every visit and check A1C every 3 months. Treatment may escalate to metformin plus two oral agents or metformin plus insulin, if necessary.
HYPOGLYCEMIA
Table 43-9 Comparison of Agents Used for Treatment of Diabetes
Agents Used to Treat Hypoglycemia
Figure 43-12. Treatment of hypoglycemia with glucose or glucagon. The blood glucose falls following administration of insulin (at time = 0). Following administration of oral glucose (10 or 20 g) or subcutaneous glucagon (at arrow marked "Rx"), the blood glucose rises. The blue band shows the recovery when glucose or glucagon was not administered. (Copyright 1993 American Diabetes Association. From Wiethop and Cryer. Diabetes Care, Vol. 16, 1993; 1131-1136. Reprinted with permission from The American Diabetes Association.)
OTHER PANCREATIC ISLET HORMONES
BIBLIOGRAPHY
chapter 44 Agents Affecting Mineral Ion Homeostasis and Bone Turnover
PHYSIOLOGY OF MINERAL ION HOMEOSTASIS
Calcium
Figure 44-1. Pools of calcium in serum. Concentrations are expressed as mg/dL on the left-hand axis and as mM on the right. The total serum calcium concentration is 10 mg/dL or 2.5 mM, divided into three pools: protein-bound (40%), complexed with small anions (10%), and ionized calcium (50%). The complexed and ionized pools represent the diffusable forms of calcium.
Figure 44-2. Schematic representation of the whole body daily turnover of calcium. (Adapted with permission from Yanagawa N, Lee DBN. Renal handling of calcium and phosphorus. In: Disorders of Bone and Mineral Metabolism (Coe FL, Favus MJ, eds.), Raven Press, New York, 1992, pp. 3–40.)
Phosphate
HORMONAL REGULATION OF CALCIUM AND PHOSPHATE HOMEOSTASIS
Figure 44-3. Calcium homeostasis and its regulation by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D. PTH has stimulatory effects on bone and kidney, including the stimulation of 1α-hydroxylase activity in kidney mitochondria leading to the increased production of 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxycholecalciferol, the monohydroxylated vitamin D metabolite (Figure 44-6). Calcitriol is the biologically active metabolite of vitamin D.
Parathyroid Hormone
Vitamin D
Figure 44-4. Photobiology and metabolic pathways of vitamin D production and metabolism.
Figure 44-5. Regulation of 1α-hydroxylase activity. Changes in the plasma levels of PTH, Ca2+, and phospate modulate the hydroxylation of 25-OH vitamin D to the active form, 1,25-dihydroxyvitamin D. 25-OHD, 25-hydroxycholecalciferol; 1,25-(OH)2-D, calcitriol; PTH, parathyroid hormone.
Calcitonin
Figure 44-6. Alternative splicing of calcitonin/calcitonin gene-related peptide (CGRP).
Figure 44-7. Comparison of calcitonins from several species. Calcitonin is a 32-amino-acid polypeptide with a disulfide bond between residues 1 and 7 and a proline-amide at the C-terminus. The figure highlights the differences in amino acid sequence between human calcitonin and calcitonins of other species; lack of an entry indicates identity with human calcitonin. Salmon calcitonin is ~20 times more potent in humans than is human calcitonin.
Fibroblast Growth Factor 23 and Klotho
BONE PHYSIOLOGY
Figure 44-8. The bone remodeling cycle. Osteoclast precursors fuse and are activated to resorb a lacuna in a previously quiescent surface. These cells are replaced by osteoblasts that deposit new bone to restore the integrity of the tissue. (Adapted with permission from Skerry TM, Gowen M. Bone cells and bone in remodelling in rheumatoid arthritis. In: Mechanisms and Models in Rheumatoid Arthritis [Henderson B, Edwards JCW, Pettipher ER, eds.], Academic Press, London, 1995, pp. 205–220.)
DISORDERS OF MINERAL HOMEOSTASIS AND BONE
Abnormal Calcium Metabolism
Figure 44-9. Receptor for activating NF- κB ligand (RANKL) and osteoclast formation. RANKL, acting on RANK, promotes osteoclast formation and subsequent resorption of bone matrix. Osteoprotegerin (OPG) binds to RANKL, reducing its binding to RANK and thereby inhibiting osteoclast differentiation.
Disturbed Phosphate Metabolism
Disorders of Vitamin D
Osteoporosis
PHARMACOLOGICAL TREATMENT OF DISORDERS OF MINERAL ION HOMEOSTASIS AND BONE METABOLISM
Hypercalcemia
THERAPEUTIC USES OF VITAMIN D
Figure 44-10. Vitamin D analogs.
Therapeutic Indications for Vitamin D
Adverse Effects of Vitamin D Therapy
CALCITONIN
BISPHOSPHONATES
Figure 44-11. Structures of pyrophosphate and bisphosphonates. The substituents (R1 and R2) on the central carbon of the bisphosphonate parent structure are shown in blue.
Available Bisphosphonates
Other Therapeutic Uses
PARATHYROID HORMONE
CALCIUM SENSOR MIMETICS: CINACALCET
Figure 44-12. Structure of cinacalcet. Cinacalcet exists as optical isomers. The R-enantiomer, which is more active, is shown.
INTEGRATED APPROACH TO PREVENTION AND TREATMENT OF OSTEOPOROSIS
Figure 44-13. Relative efficacy of different therapeutic interventions on bone mineral density of the lumbar spine. Teriparatide (40 µg) (Neer et al., 2001), PTH (25 µg) + estradiol, alendronate (10 mg), estradiol (0.625 mg/day), raloxifene (120 mg), calcitonin (200 IU). Typical results with placebo treatment underscore the inexorable bone loss without intervention. Some of the indicated treatment interventions involved combination therapy, and absolute comparisons should not be made. For additional references, see legend to Figure 61-13 in the 11th edition of this text.
Combination Therapies
FLUORIDE
CLINICAL SUMMARY
BIBLIOGRAPHY
Section VI Drugs Affecting Gastrointestinal Function
chapter 45 Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease
PHYSIOLOGY OF GASTRIC SECRETION
Figure 45-1. Physiological and pharmacological regulation of gastric secretion: the basis for therapy of acid-peptic disorders. Shown are the interactions among an enterochromaffin-like (ECL) cell that secretes histamine, a ganglion cell of the enteric nervous system (ENS), a parietal cell that secretes acid, and a superficial epithelial cell that secretes mucus and bicarbonate. Physiological pathways, shown in solid black, may be stimulatory (+) or inhibitory (−). 1 and 3 indicate possible inputs from postganglionic cholinergic fibers; 2 shows neural input from the vagus nerve. Physiological agonists and their respective membrane receptors include acetylcholine (ACh), muscarinic (M), and nicotinic (N) receptors; gastrin, cholecystokinin receptor 2 (CCK2); histamine (HIST), H2 receptor; and prostaglandin E2 (PGE2), EP3 receptor. A red indicates targets of pharmacological antagonism. A light blue dashed arrow indicates a drug action that mimics or enhances a physiological pathway. Shown in red are drugs used to treat acid-peptic disorders. NSAIDs are nonsteroidal anti-inflammatory drugs, which can induce ulcers via inhibition of cyclooxygenase.
PROTON PUMP INHIBITORS
Figure 45-2. Proton pump inhibitors. A. Inhibitors of gastric H+, K+-ATPase (proton pump). B. Conversion of omeprazole to a sulfenamide in the acidic secretory canaliculi of the parietal cell. The sulfenamide interacts covalently with sulfhydryl groups in the proton pump, thereby irreversibly inhibiting its activity. The other three proton pump inhibitors undergo analogous conversions.
H2 RECEPTOR ANTAGONISTS
Table 45-1 Intravenous Doses of H2 Receptor Antagonists
Figure 45-3. Histamine and H2 receptor antagonists.
TOLERANCE AND REBOUND WITH ACID-SUPPRESSING MEDICATIONS
AGENTS THAT ENHANCE MUCOSAL DEFENSE
Prostaglandin Analogs: Misoprostol
SUCRALFATE
ANTACIDS
Table 45-2 Composition and Acid Neutralizing Capacities of Popular Antacid Preparations
Other Acid Suppressants and Cytoprotectants
SPECIFIC ACID-PEPTIC DISORDERS AND THERAPEUTIC STRATEGIES
Gastroesophageal Reflux Disease
Figure 45-4. Comparative success of therapy with proton pump inhibitors and H2 receptor antagonists. Data show the effects of a proton pump inhibitor (given once daily) and an H2 receptor antagonist (given twice daily) in elevating gastric pH to the target ranges (i.e., pH 3 for duodenal ulcer, pH 4 for GERD, and pH 5 for antibiotic eradication of H. pylori).
Figure 45-5. General guidelines for the medical management of gastroesophageal reflux disease (GERD). Only medications that suppress acid production or that neutralize acid are shown. (Adapted from Wolfe and Sachs, 2000, with permission from Elsevier. Copyright © Elsevier.)
Table 45-3 Antisecretory Drug Regimens for Treatment and Maintenance of GERD
PEPTIC ULCER DISEASE
Table 45-4 Recommendations for Treatment of Gastroduodenal Ulcers
Table 45-5 Therapy of Helicobacter pylori Infection
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 46 Treatment of Disorders of Bowel Motility and Water Flux; Anti-Emetics; Agents Used in Biliary and Pancreatic Disease
INTRODUCTION TO GASTROINTESTINAL MOTILITY
Generation and Regulation of GI Activity
Figure 46-1. The neuronal network that initiates and generates the peristaltic response. Mucosal stimulation leads to release of serotonin by enterochromaffin cells (8), which excites the intrinsic primary afferent neurons (1), which then communicate with ascending (2) and descending (3) interneurons in the local reflex pathways. The reflex results in contraction at the oral end via the excitatory motor neuron (6) and aboral relaxation via the inhibitory motor neuron (5). The migratory myoelectric complex (see text) is shown here as being conducted by a different chain of interneurons (4). Another intrinsic primary afferent neuron with its cell body in the submucosa also is shown (7). MP, myenteric plexus; CM, circular muscle; LM, longitudinal muscle; SM, submucosa; Muc, mucosa. (Adapted from Kunze and Furness, 1999, with permission from Annual Reviews. http://www.annualreviews.org.)
Excitation-Contraction Coupling in GI Smooth Muscle
OVERVIEW OF FUNCTIONAL AND MOTILITY DISORDERS OF THE BOWEL
PROKINETIC AGENTS AND OTHER STIMULANTS OF GI CONTRACTILITY
Dopamine Receptor Antagonists
Domperidone; D2 Receptor Antagonists
Serotonin Receptor Agonists
Figure 46-2. Ligands of 5-HT3 and 5-HT4 receptors modulating GI motility.
Motilides
Miscellaneous Agents for Stimulating Motility
Agents that Suppress Motility
LAXATIVES, CATHARTICS, AND THERAPY FOR CONSTIPATION
Figure 46-3. The approximate volume and composition of fluid that traverses the small and large intestines daily. Of the 9 L of fluid typically presented to the small intestine each day, 2 L are from the diet and 7 L are from secretions (salivary, gastric, pancreatic, and biliary). The absorptive capacity of the colon is 4–5 L per day.
Table 46-1 Classification of Laxatives
Table 46-2 Summary of Effects of Some Laxatives on Bowel Function
Dietary Fiber and Supplements
Table 46-3 Classification and Comparison of Representative Laxatives
Osmotically Active Agents
Table 46-4 Properties of Different Dietary Fibers
Stool-Wetting Agents and Emollients
Stimulant (Irritant) Laxatives
Prokinetic and Other Agents for Constipation
Opioid-Induced Constipation
Post-operative Ileus
Enemas and Suppositories
ANTI-DIARRHEAL AGENTS
Anti-Motility and Anti-Secretory Agents
Other Agents
IRRITABLE BOWEL SYNDROME (IBS)
Alosetron and Other 5-HT3 Antagonists
ANTI-SPASMODICS AND OTHER AGENTS
ANTI-NAUSEANTS AND ANTI-EMETIC AGENTS
Nausea and Vomiting
5-HT3 Receptor Antagonists
Figure 46-4. Pharmacologist's view of emetic stimuli. Myriad signaling pathways lead from the periphery to the emetic center. Stimulants of these pathways are noted in italics. These pathways involve specific neurotransmitters and their receptors (bold type). Receptors are shown for dopamine (D2), acetylcholine (muscarinic, M), histamine (H1), cannabinoids (CB1), substance P (NK1), and 5-hydroxytryptamine (5-HT3). Some of these receptors also may mediate signaling in the emetic center.
Tabel 46-5 General Classification of Anti-emetic Agents
Table 46-6 Receptor Specificity of Anti-emetic Agents
Dopamine-Receptor Antagonists
Table 46-7
Antihistamines
Anticholinergic Agents
Substance P Receptor Antagonists
Cannabinoids
Table 46-8 5-HT3 Antagonists in Chemotherapy-Induced Nausea/Emesis
Glucocorticoids and Anti-Inflammatory Agents
Benzodiazepines
Phosphorated Carbohydrate Solutions
AGENTS USED FOR MISCELLANEOUS GI DISORDERS
Chronic Pancreatitis and Steatorrhea
Enzyme Deficiencies
BILE ACIDS
Figure 46-5. Major bile acids in adults.
ANTI-FLATULENCE AGENTS
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 47 Pharmacotherapy of Inflammatory Bowel Disease
PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE
Table 47-1 Medications Commonly Used to Treat Inflammatory Bowel Disease
Figure 47-1. Proposed pathogenesis of inflammatory bowel disease and target sites for pharmacological intervention. Shown are the interactions among bacterial antigens in the intestinal lumen and immune cells in the intestinal wall. If the epithelial barrier is impaired, bacterial antigens can gain access to antigen-presenting cells (APC) such as dendritic cells in the lamina propria. These cells then present the antigen(s) to CD4+ lymphocytes and also secrete cytokines such interleukin (IL)-12 and IL-18, thereby inducing the differentiation of TH1 cells in Crohn's disease (or, under the control of IL-4, type 2 helper T cells [TH2] in ulcerative colitis). The balance of pro-inflammatory and anti-inflammatory events is also governed by regulatory TH17 and TReg cells, both of which serve to limit immune and inflammatory responses in the GI tract. Transforming growth factor (TGF) β and IL-6 are important cytokines that drive the expansion of the regulatory T cell subsets. The TH1 cells produce a characteristic array of cytokines, including interferon (IFN) γ and TNFα, which in turn activate macrophages. Macrophages positively regulate TH1 cells by secreting additional cytokines, including IFNγ and TNFα. Recruitment of a variety of leukocytes is mediated by activation of resident immune cells including neutrophils. Cell adhesion molecules such as integrins are important in the infiltration of leukocytes and novel biological therapeutic strategies aimed at blocking leukocyte recruitment are effective at reducing inflammation. General immunosuppressants (e.g., glucocorticoids, thioguanine derivatives, methotrexate, and cyclosporine) affect multiple sites of inflammation. More site-specific intervention involve intestinal bacteria (antibiotics, prebiotics, and probiotics) and therapy directed at TNFα or IL-12 (see text for further details).
MESALAMINE (5-ASA)-BASED THERAPY
Figure 47-2. Structures of sulfasalazine and related agents. The red N atoms indicate the diazo linkage that is cleaved to generate the active moiety.
Figure 47-3. Metabolic fates of the different oral formulations of mesalamine (5-ASA). Chemical structures are in Figure 47-2.
Figure 47-4. Sites of release of mesalamine (5-ASA) in the GI tract from different oral formulations.
GLUCOCORTICOIDS
IMMUNOSUPPRESSIVE AGENTS
Thiopurine Derivatives
Figure 47-5. Metabolism of azathioprine and 6-mercaptopurine. HGPRT, hypoxanthine-guanine phosphoribosyl transferase; TPMT, thiopurine methyltransferase; XO, xanthine oxidase. The activities of these enzymes vary among humans because genetic polymorphisms are expressed differentially, explaining responses and side effects when azathioprine-mercaptopurine therapy is employed (see text for details).
Methotrexate
Cyclosporine
BIOLOGICAL THERAPIES
ANTIBIOTICS AND PROBIOTICS
SUPPORTIVE THERAPY IN INFLAMMATORY BOWEL DISEASE
THERAPY OF INFLAMMATORY BOWEL DISEASE DURING PREGNANCY
CLINICAL SUMMARY
BIBLIOGRAPHY
Section VII Chemotherapy of Microbial Diseases
chapter 48 General Principles of Antimicrobial Therapy
SCIENTIFIC BASIS OF ANTIMICROBIAL CHEMOTHERAPY
Figure 48-1. Inhibitory sigmoid Emax curve. CFU, colony-forming units.
(Equation 48-1)
THE PHARMACOKINETIC BASIS OF ANTIMICROBIAL THERAPY
(Equation 48-2)
(Equation 48-3)
(Equation 48-4)
(Equation 48-5)
(Equation 48-6)
(Equation 48-7)
(Equation 48-8)
(Equation 48-9)
Figure 48-2. Diagrammatic depiction of a multi-compartment model.
(Equation 48-10)
(Equation 48-11)
IMPACT OF SUSCEPTIBILITY TESTING ON SUCCESS OF ANTIMICROBIAL AGENTS
Figure 48-3. Changes in sigmoid Emax model with increases in drug resistance. Increase in resistance may show changes in IC50 (panel A: the IC50 increases from 70 (orange line) to 100 (green line), to 140 (blue line)) or decrease in Emax (panel B: efficacy decreases from full response (orange line) to 70% (green line))
BASIS FOR SELECTION OF DOSE AND DOSING SCHEDULE
Figure 48-4. Effect of different dose schedules on shape of concentration-time curve. The total AUC for the fractionated dose in curve B is determined by adding AUC0–8h, AUC8–16h and AUC16–24h, which adds up to the same AUC0–24h in curve A. The time that the drug concentration exceeds MIC in curve B is also determined by adding up T1>MIC, T2>MIC, and T3>MIC, which results in a fraction greater than that for curve A.
Figure 48-5. Aantimicrobial therapy-disease progression timeline. Stages of disease progression are below the horizontal arrow; categories of antimicrobial therapy are above the arrow.
TYPES AND GOALS OF ANTIMICROBIAL THERAPY
MECHANISMS OF RESISTANCE TO ANTIMICROBIAL AGENTS
EVOLUTIONARY BASIS OF RESISTANCE EMERGENCE
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 49 Chemotherapy of Malaria
BIOLOGY OF MALARIAL INFECTION
Figure 49-1. Life cycle of malaria parasites.
Clinical Manifestations of Malaria
CLASSIFICATION OF ANTIMALARIAL AGENTS
Table 49-1 Malarial Parasite Developmental Stages Targeted by Antimalarial Drugs
ARTEMISININ AND DERIVATIVES
Table 49-2 Regimens for the Prevention of Malaria in Non-immune Individuals
Table 49-3 Regimens for the Treatment of Malaria
Table 49-4 Regimen for Presumptive Self-Treatment of Malaria
Figure 49-2. Chemical structure of antimalarial quinolines and related compounds.
ATOVAQUONE
DIAMINOPYRIMIDINES
PROGUANIL
QUINOLINES AND RELATED COMPOUNDS
Chloroquine and Hydroxychloroquine
Figure 49-3. Malaria-endemic countries in the Americas (bottom) and in Africa, the Middle East, Asia, and the South Pacific (top), 2007. CAR, Central African Republic; DCOR, Democratic Republic of the Congo; UAE, United Arab Emirates. (Reproduced with permission from Anthony S. Fauci, Eugene Braunwald, Dennis L Kasper, Stephen L Hauser, Dan L Longo, J Larry Jameson, and Joseph Loscalzo, Eds. Harrison's Principles of Internal Medicine, 17 ed. McGraw-Hill, Inc., New York, 2008. Figure 203-2, p. 1282.)
Quinine and Quinidine
Mefloquine
Primaquine
SULFONAMIDES AND SULFONES
TETRACYCLINES AND OTHER ANTIBIOTIC AGENTS
PRINCIPLES AND GUIDELINES FOR CHEMOPROPHYLAXIS AND CHEMOTHERAPY OF MALARIA
Table 49-5 Criteria for the Diagnosis of Malaria
Figure 49-4. Approach to the treatment of malaria. Atovaquone-proguanil, mefloquine, artemether-lumefantrine, tetracycline, and doxycycline are not indicated during pregnancy. Tetracycline and doxycycline are not indicated in children <8 years of age. G6PD, glucose-6-phosphate dehydrogenase. (Adapted from Griffith KS, Lewis LS, Mali S, Parise ME. Treatment of malaria in the United States: A systematic review. JAMA, 297(20):2264–77, 2007, with permission of the American Medical Association © 2007. All rights reserved.)
New Targets, New Drugs
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 50 Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections
INTRODUCTION TO PROTOZOAL INFECTIONS OF HUMANS
ANTI-PROTOZOAL DRUGS
Amphotericin B
Chloroquine
Diloxanide Furoate
Eflornithine
Emetine and Dehydroemetine
Fumagillin
8-Hydroxyquinolines
Melarsoprol
Metronidazole
Miltefosine
Nifurtimox and Benznidazole
Nitazoxanide
Paromomycin
Pentamidine
Quinacrine
Sodium Stibogluconate
Suramin
BIBLIOGRAPHY
chapter 51 Chemotherapy of Helminth Infections
Figure 51-1. Relative incidence of helminth infections worldwide.
HELMINTH INFECTIONS AND THEIR TREATMENT
Nematodes (Roundworms)
Hookworm
Cestodes (Flatworms)
Trematodes (Flukes)
ANTHELMINTIC DRUGS
Benzimidazoles (BZ)
Table 51-1 Structure of the Benzimidazoles
Diethylcarbamazine (DEC)
Doxycycline
Ivermectin
Therapeutic Uses
Praziquantel
Metrifonate
Oxamniquine
Niclosamide
Piperazine
Pyrantel Pamoate
BIBLIOGRAPHY
chapter 52 Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections
SULFONAMIDES
Effects on Microbes
Figure 52-1. Structural formulas of selected sulfonamides and para-aminobenzoic acid. The N of the para-NH2 group is designated as N4; that of the amide NH2, as N1.
Figure 52-2. Steps in folate metabolism blocked by sulfonamides and trimethoprim.
Absorption, Fate, and Excretion
Pharmacological Properties of Individual Sulfonamides
Rapidly Absorbed and Eliminated Sulfonamides
Table 52-1 Classes of Sulfonamides
Poorly Absorbed Sulfonamides
Sulfonamides for Topical Use
Long-Acting Sulfonamides
Sulfonamide Therapy
Untoward Reactions to Sulfonamides
Disorders of the Hematopoietic System.
TRIMETHOPRIM-SULFAMETHOXAZOLE
Therapeutic Uses.
THE QUINOLONES
Table 52-2 Structural Formulas of Selected Quinolones and Fluoroquinolones
Figure 52-3. Model of the formation of negative DNA supercoils by DNA gyrase. The enzyme binds to two segments of DNA (1), creating a node of positive (+) superhelix. The enzyme then introduces a double-strand break in the DNA and passes the front segment through the break (2). The break is then resealed (3), creating a negative (-) supercoil. Quinolones inhibit the nicking and closing activity of the gyrase and, at higher concentrations, block the decatenating activity of topoisomerase IV. From Cozzarelli NR. DNA gyrase and the supercoiling of DNA. Science, 1980, 207:953–960. Reprinted with permission from AAAS.
Therapeutic Uses
ANTISEPTIC AND ANALGESIC AGENTS FOR URINARY TRACT INFECTIONS
BIBLIOGRAPHY
chapter 53 Penicillins, Cephalosporins, and Other β-Lactam Antibiotics
THE PENICILLINS
Figure 53-1. Structure of penicillins and products of their enzymatic hydrolysis.
Figure 53-2. Action of β-lactam antibiotics in Staphylococcus aureus. The bacterial cell wall consists of glycopeptide polymers (a NAM-NAG amino-hexose backbone) linked via bridges between amino acid side chains. In S. aureus, the bridge is (Gly)5-d-Ala between lysines. The cross-linking is catalyzed by a transpeptidase, the enzyme that penicillins and cephalosporins inhibit. NAM, N-acetyl-muramic acid; NAG, N-acetyl-glucosamine.
Figure 53-3. A. Comparison of the structure and composition of gram-positive and gram-negative cell walls. (Fig. 4-11, pg 83 from Microbiology: An Introduction, 3rd ed. By Gerard J. Tortora, Berdell R. Funke, and Christine L. Case. Copyright © 1989, 1986, 1982 by the Benjamin/Cummings Company, Inc. Reprinted by permission of Pearson Education, Inc.) B. Schematic of Penicillin Binding Protein 2(PBP2) from S. aureus. PBP2 has two enzymatic activities that are crucial to synthesis of the peptidoglycan layers of bacterial cell walls: a transpeptidase that crosslinks amino acid side chains, and a glycosyltransferase that links subunits of the glycopeptide polymer (see Figure 53-2). The transpeptidase and glycosyltransferase domains are separated by a linker region. The glycosyltransferase is thought to be partially embedded in the membrane.
Figure 53-4. Mosaic penicillin-binding protein (PBP) 2B genes in penicillin-resistant pneumococci. The divergent regions in the PBP2B genes of seven resistant pneumococci from different countries are shown. These regions have been introduced from at least three sources, one of which appears to be Streptococcus mitis. The approximate percent sequence divergence of the divergent regions from the PBP2B genes of susceptible pneumococci is shown. (From Spratt BG. Resistance to antibiotics mediated by target alterations. Science, 1994, 264:388–393. Reprinted with permission from AAAS.)
Figure 53-5. Antibiotic efflux pumps of gram-negative bacteria. Multidrug efflux pumps traverse both the inner and outer membranes of gram-negative bacteria. The pumps are composed of a minimum of three proteins and are energized by the proton motive force. Increased expression of these pumps is an important cause of antibiotic resistance. (Reprinted with permission from the University of Chicago Press. Nikaido H. Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis, 1998, 27(suppl I):S32–S41. © 1998 by the Infectious Diseases Society of America. All rights reserved.)
Classification of the Penicillins and Summary of Their Pharmacological Properties
Penicillin G and Penicillin V
Absorption
Therapeutic Uses
The Penicillinase-Resistant Penicillins
The Aminopenicillins: Ampicillin, Amoxicillin, and Their Congeners
Table 53-1 Chemical Structures and Major Properties of Various Penicillins
Therapeutic Indications for the Aminopenicillins
Anti-Pseudomonal Penicillins: The Carboxypenicillins and the Ureidopenicillins
Untoward Reactions to Penicillins
THE CEPHALOSPORINS
Table 53-2 Names, Structural Formulas, Dosage, and Dosage Forms of Selected Cephalosporins and Related Compounds
Table 53-3 Cephalosporin Generations
Specific Agents
Third-Generation Cephalosporins with Good Activity Against Pseudomonas
OTHER β-LACTAM ANTIBIOTICS
Carbapenems
β-LACTAMASE INHIBITORS
BIBLIOGRAPHY
chapter 54 Aminoglycosides
Figure 54-1. Sites of activity of various plasmid-mediated enzymes capable of inactivating aminoglycosides. The red X indicates regions of the molecules that are protected from the designated enzyme. In gentamicin C1, R1=R2=CH3; in gentamicin C2, R1=CH3, R2=H; in gentamicin C1a, R1=R2=H. (Reproduced with permission from Moellering RC Jr. Microbiological considerations in the use of tobramycin and related aninoglycosidic aminocyclitol antibiotics. MJA 1977;2S:4–8. Copyright 1977. The Medical Journal of Australia.)
Figure 54-2. Effects of aminoglycosides on protein synthesis. A. Aminoglycoside (represented by red circles) binds to the 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA. As 30S–50S complexes downstream complete translation ofmRNAand detach, the abnormal initiation complexes, so-called streptomycin monosomes, accumulate, blocking further translation of the message.Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to B, premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein or C, incorporation of incorrect amino acids (indicated by the red X), resulting in the production of abnormal or nonfunctional proteins.
Table 54-1 Typical Minimal Inhibitory Concentrations of Aminoglycosides That Will Inhibit 90% (MIC90) of Clinical Isolates for Several Species
Absorption, Distribution, Dosing, and Elimination of the Aminoglycosides
Table 54-2 Algorithm for Dose Reduction of Aminoglycosides Based on Calculated Creatinine Clearance
Figure 54-3. Plasma concentrations (µg/mL) after administration of 5.1 mg/kg of gentamicin intravenously to a hypothetical patient either as a single dose (every 24h) or as three divided doses (every 8h). The threshold for toxicity has been chosen to correspond to a plasma concentration of 2 µg/mL, the maximum recommended. The high-dose, extended-interval (once-daily) regimen produces a 3-fold higher plasma concentration, which enhances efficacy that otherwise might be compromised due to prolonged sub-MIC concentrations later in the dosing interval compared with the every-8-hours regimen. The once-daily regimen provides a 12-hour period during which plasma concentrations are below the threshold for toxicity, thereby minimizing the toxicity that otherwise might result from the high plasma concentrations early on. The every-8-hours regimen, in contrast, provides only a brief period during which plasma concentrations are below the threshold for toxicity.
Untoward Effects
Therapeutic Uses of Gentamicin and Other Aminoglycosides
Gentamicin
Tobramycin
Amikacin
Netilmicin
Streptomycin
Kanamycin
Neomycin
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 55 Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents
TETRACYCLINES AND GLYCYLCYCLINES
Table 55-1 Structural Formulas of the Tetracyclines
Table 55-2 Activity of Selected Antimicrobials Against Key Gram-positive Pathogens
Figure 55-1. Inhibition of bacterial protein synthesis by tetracyclines. Messenger RNA (mRNA) attaches to the 30S subunit of bacterial ribosomal RNA. The P (peptidyl) site of the 50S ribosomal RNA subunit contains the nascent polypeptide chain; normally, the aminoacyl tRNA charged with the next amino acid (aa) to be added to the chain moves into the A (acceptor) site, with complementary base pairing between the anticodon sequence of tRNA and the codon sequence of mRNA. Tetracyclines inhibit bacterial protein synthesis by binding to the 30S subunit and blocking tRNA binding to the A site.
Absorption, Distribution, and Excretion
Untoward Effects
CHLORAMPHENICOL
Figure 55-2. Inhibition of bacterial protein synthesis by chloramphenicol. Chloramphenicol binds to the 50S ribosomal subunit at the peptidyltransferase site and inhibits the transpeptidation reaction. Chloramphenicol binds to the 50S ribosomal subunit near the site of action of clindamycin and the macrolide antibiotics. These agents interfere with the binding of chloramphenicol and thus may interfere with each other's actions if given concurrently. See Figure 55-1 and its legend for additional information.
MACROLIDES AND KETOLIDES
Figure 55-3. Inhibition of bacterial protein synthesis by the macrolide antibiotics erythromycin, clarithromycin, and azithromycin. Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by binding reversibly to the 50S ribosomal subunits of sensitive organisms. Erythromycin appears to inhibit the translocation step such that the nascent peptide chain temporarily residing at the A site of the transferase reaction fails to move to the P, or donor, site. Alternatively, macrolides may bind and cause a conformational change that terminates protein synthesis by indirectly interfering with transpeptidation and translocation. See Figure 55-1 and its legend for additional information.
Absorption, Distribution, and Excretion.
Untoward Effects.
LINCOSAMIDES (CLINDAMYCIN)
Absorption, Distribution, and Excretion
Untoward Effects.
STREPTOGRAMINS (QUINUPRISTIN/ DALFOPRISTIN)
OXAZOLIDINONES (LINEZOLID)
Untoward Effects
AMINOCYCLITOLS (SPECTINOMYCIN)
POLYMYXINS
Therapeutic Uses and Dosage
GLYCOPEPTIDES (VANCOMYCIN AND TEICOPLANIN)
Figure 55-4. Inhibition of bacterial cell wall synthesis: vancomycin and β-lactam agents. Vancomycin inhibits the polymerization or transglycosylase reaction (A) by binding to the d-alanyl-d-alanine terminus of the cell wall precursor unit attached to its lipid carrier and blocks linkage to the glycopeptide polymer (indicated by the subscript n). These (NAM-NAG)n peptidoglycan polymers are located within the cell wall. Van A-type resistance is due to expression of enzymes that modify cell wall precursor by substituting a terminal D-lactate for D-alanine, reducing vancomycin binding affinity by 1000 times. β-Lactam antibiotics inhibit the cross-linking or transpeptidase reaction (B) that links glycopeptide polymer chains by formation of a cross-bridge with the stem peptide (the five glycines in this example) of one chain, displacing the terminal d-alanine of an adjacent chain. See also Figure 53-3.
Absorption, Distribution, and Excretion
LIPOPEPTIDES (DAPTOMYCIN)
BACITRACIN
MUPIROCIN
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 56 Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy
ANTI-MYCOBACTERIAL DRUGS
Rifamycins: Rifampin, Rifapentine, and Rifabutin
Table 56-1 Pathogenic Mycobacterial Rapid and Slow Growers (Runyon Classification)
Figure 56-1. Mechanisms of action of established and experimental drugs used for the chemotherapy of mycobacterial infections. Shown at the top are the sites of action of approved drugs for the chemotherapy of mycobacterial diseases. Rifamycin is used as a generic term for several drugs, of which rifampin is used most frequently. Also included are two experimental drugs now under investigation: TMC-207 and PA-824. Clofazimine, whose mode of action is not understood, is omitted.
Figure 56-2. Mechanisms of resistance of Mycobacteria to different chemotherapeutic drugs. Shown are the various mechanisms by which mycobacteria resist antibacterial effects of the currently approved chemotherapeutic agents.
Table 56-2 Population Pharmacokinetic Parameter Estimates for Antimycobacterial Drugs in Adult Patients
Table 56-3 Pharmacokinetic Parameters of Rifampin, Rifabutin, and Rifapentine
Pyrazinamide
Isoniazid
Figure 56-3. Metabolism and activation of isoniazid. The pro-drug isoniazid is metabolized in humans by NAT2 isoforms to its principal metabolite, N-acetyl isoniazid, which is excreted by the kidney. Isoniazid diffuses into mycoplasma where it is "activated" by KatG (oxidase/peroxidase) to the nicotinoyl radical, which reacts spontaneously with NAD+ or NADP+ to produce adducts that inhibit important enzymes in cell-wall and nucleic acid synthesis. DHFR, dihydrofolate reductase.
Figure 56-4. Multi-modal distribution of INH clearance due to NAT2 polymorphisms. Twenty-four male volunteers were given INH (250 mg orally [3.3 ± 0.5 mg/kg; all subjects within 10% of estimated lean body mass]) and the time courses of plasma levels (Cp) were assessed. (Modified with permission from Peloquin CA et al. Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide. Antimicrob Agents Chemother; 1997, 41:2670. With permission from American Society for Microbiology.) A. Frequency distribution of elimination half-times. Plotting elimination half-times (t1/2) as a frequency distribution demonstrates a group of 8 subjects with t1/2 values < 1.5 hours (mean = 1.2 hours), the fast acetylators, and a group of 16 with t1/2 values > 2 hours (mean = 3.3 hours), the slow acetylators. B. Time course of plasma levels. The mean data (Cp vs time after administration) fall into two major groups (see panel A). Both groups reached CPmax at 1 hour. One group (red line) achieved a higher Cp (3.6 µg/mL) with a mean elimination t1/2 = 3.3 hours (slow acetylators); the other group (green line) reached a lower maximal Cp (2.3 µg/mL) with a mean elimination t1/2 = 1.2 hours (fast acetylators). Variation in expression of active and defective polymorphic forms of NAT2 characterize the fast and slow acetylators. Slow acetylators may be a greater risk for adverse effects from INH, sulfonamides, and procainamide, whereas fast acetylators may have diminished responses to standard doses of these agents but greater risk from bioactivation by NAT2 of arylamine/hydrazine carcinogens. Recently, researchers have identified three elimination subgroups for INH metabolism, fast, slow, and intermediate (codominant fast and slow alleles).
Table 56-4 Isoniazid-Drug Interactions via Inhibition and Induction of CYPs
Ethambutol
Aminoglycosides: Streptomycin, Amikacin, and Kanamycin
Clofazimine
Fluoroquinolones
TMC-207 (R207910)
PA-824
Ethionamide
Para-Aminosalicylic Acid
Cycloserine
Capreomycin
Macrolides
Dapsone
Figure 56-5. Effects of antimicrobials on folate metabolism and deoxynucleotide synthesis.
PRINCIPLES OF ANTITUBERCULOSIS CHEMOTHERAPY
Types of Antituberculosis Therapy
PRINCIPLES OF THERAPY AGAINST MYCOBACTERIUM AVIUM COMPLEX
Therapy of MAC Pulmonary Infection
Therapy for Disseminated M. Avium Complex
PRINCIPLES OF ANTI-LEPROSY THERAPY
Types of Anti-Leprosy Therapy
Table 56-5 Drugs Used in the Treatment of Mycobacteria Other Than for Tuberculosis, Leprosy, or MAC
Definitive Therapy; Standard Therapy
Therapy for Other Nontuberculous Mycobacteria
CLINICAL SUMMARY
BIBLIOGRAPHY
chapter 57 Antifungal Agents
SYSTEMIC ANTIFUNGAL AGENTS: SYSTEMIC DRUGS FOR DEEPLY INVASIVE FUNGAL INFECTIONS
Amphotericin B
Figure 57-1. Sites of action of antifungal drugs. Amphotericin B and other polyenes, such as nystatin, bind to ergosterol in fungal cell membranes and increase membrane permeability. The imidazoles and triazoles, such as itraconazole and fluconazole, inhibit 14-α-sterol demethylase, prevent ergosterol synthesis, and lead to the accumulation of 14-α-methylsterols. The allylamines, such as naftifine and terbinafine, inhibit squalene epoxidase and prevent ergosterol synthesis. The echinocandins, such as caspofungin, inhibit the formation of glucans in the fungal cell wall.
Table 57-1 Pharmacotherapy of Mycoses
Table 57-2 Pharmocokinetic Parameters for Amphotericin B Formulations after Multiple Administrations in Humans
Flucytosine
Figure 57-2. Action of flucytosine in fungi. Flucytosine is transported by cytosine permease into the fungal cell, where it is deaminated to 5-fluorouracil (5-FU). The 5-FU is then converted to 5-fluorouracil-ribose monophosphate (5-FUMP) and then is either converted to 5-fluorouridine triphosphate (5-FUTP) and incorporated into RNA or converted by ribonucleotide reductase to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP), which is a potent inhibitor of thymidylate synthase. 5-FUDP, 5-fluorouridine-5′-diphosphate; dUMP, deoxyuridine-5′-monophosphate; dTMP, deoxythymidine-5′-monophosphate.
Imidazoles and Triazoles
Ketoconazole
Itraconazole
Table 57-3 Interaction of Azole Antifungal Agents with Hepatic CYPs
Table 57-4 Drugs Exhibiting Elevated Plasma Concentrations When Co-Administered with Azole Anti-Fungal Agents
Table 57-5 Some Drugs that Decrease Azole Concentration When Co-Administered
Table 57-6 Some Additional Contraindicated Azole Drug Combinations
Fluconazole
Voriconazole
Posaconazole
Isavuconazole
Echinocandins
Figure 57-3. The fungal cell wall and membrane and the action of echinocandins. The strength of the fungal cell wall is maintained by fibrillar polysaccharides, largely β-1,3-glucan and chitin, which bind covalently to each other and to proteins. A glucan synthase complex in the plasma membrane catalyzes the synthesis of beta-1,3-glucan; the glucan is extruded into the periplasm and incorporated into the cell wall. Echinocandins inhibit the activity of the glucan synthase complex, resulting in loss of the structural integrity of the cell wall. A subunit of glucan synthase designated Fks1p is thought to be the target of the echinocandin. Mutations in Fks1p, coded for by FSK1, cause resistance to echinocandins.
Caspofungin
Table 57-7 Pharmacokinetics of Echinocandins in Humans
Micafungin
Anidulafungin
Griseofulvin
Terbinafine
Topical Antifungal Agents
Imidazoles and Triazoles for Topical Use
Clotrimazole
Econazole
Miconazole
Terconazole and Butoconazole
Tioconazole
Oxiconazole, Sulconazole, and Sertaconazole
Ketoconazole
Ciclopirox Olamine
Haloprogin
Tolnaftate
Naftifine
Terbinafine
Butenafine
Polyene Antifungal Antibiotics
Miscellaneous Antifungal Agents
BIBLIOGRAPHY
chapter 58 Antiviral Agents (Nonretroviral)
ANTI-HERPESVIRUS AGENTS
Table 58-1 Stages of Virus Replication and Possible Targets of Action of Antiviral Agents
Acyclovir and Valacyclovir
Figure 58-1. Replicative cycles of DNA (A) and RNA (B) viruses. The replicative cycles of herpesvirus (A) and influenza (B) are examples of DNA-encoded and RNA-encoded viruses, respectively. Sites of action of antiviral agents also are shown. Key: mRNA = messenger RNA; cDNA = complementary DNA; vRNA = viral RNA; DNAp = DNA polymerase; RNAp = RNA polymerase; cRNA = complementary RNA. The symbol indicates a block to virus growth. A. Replicative cycles of herpes simplex virus, a DNA virus, and the probable sites of action of antiviral agents. Herpesvirus replication is a regulated multistep process. After infection, a small number of immediate-early genes are transcribed; these genes encode proteins that regulate their own synthesis and are responsible for synthesis of early genes involved in genome replication, such as thymidine kinases, DNA polymerases, etc. After DNA replication, the bulk of the herpesvirus genes (called late genes) are expressed and encode proteins that either are incorporated into or aid in the assembly of progeny virions. B. Replicative cycles of influenza, an RNA virus, and the loci for effects of antiviral agents. The mammalian cell shown is an airway epithelial cell. The M2 protein of influenza virus allows an influx of hydrogen ions into the virion interior, which in turn promotes dissociation of the RNP (ribonuclear protein) segments and release into the cytoplasm (uncoating). Influenza virus mRNA synthesis requires a primer cleared from cellular mRNA and used by the viral RNAp complex. The neuraminidase inhibitors zanamivir and oseltamivir specifically inhibit release of progeny virus. Small capitals indicate virus proteins.
Table 58-2 Nomenclature of Antiviral Agents
Figure 58-2. Chemical Structures of Anti-Herpes Drugs.
Figure 58-3. Mechanism of Action of Acyclovir in Cells Infected by Herpes Simplex Virus. A herpes simplex virion is shown attaching to a susceptible host cell, fusing its envelope with the cell membrane, and releasing naked capsids that deliver viral DNA into the nucleus, where it initiates synthesis of viral DNA. Acyclovir molecules entering the cell are converted to acyclovir monophosphate by virusinduced thymidine kinase. Host-cell enzymes add two more phosphates to form acyclovir triphosphate, which is transported into the nucleus. After the herpes DNA polymerase cleaves pyrophosphate from acyclovir triphosphate (indicated by the red arrow in the inset), viral DNA polymerase inserts acyclovir monophosphate rather than 2′-deoxyguanosine monophosphate into the viral DNA (indicated by black arrows in the inset). Further elongation of the chain is impossible because acyclovir monophosphate lacks the 3′ hydroxyl group necessary for the insertion of an additional nucleotide, and the exonuclease associated with the viral DNA polymerase cannot remove the acyclovir moiety. In contrast, ganciclovir and penciclovir have a 3′ hydroxyl group; therefore, further synthesis of viral DNA is possible in the presence of these drugs. Foscarnet acts at the pyrophosphate-binding site of viral DNA polymerase and prevents cleavage of the pyrophosphate from nucleoside triphosphates, thus stalling further primer template extension. The red bands between the viral DNA strands in the inset indicate hydrogen bonding of the base pairs. (Adapted with permission from Balfour HH. Antiviral drugs. N Engl J Med, 1999, 340:1255–1268. Copyright © 1999. Massachusetts Medical Society. All rights reserved.)
Cidofovir
Famciclovir and Penciclovir
Fomivirsen
Foscarnet
Ganciclovir and Valganciclovir
Docosanol
Idoxuridine
Trifluridine
ANTI-INFLUENZA AGENTS
Amantadine and Rimantadine
Figure 58-4. Chemical Structures of the Anti-Influenza Drugs.
Oseltamivir
Table 58-3 Pharmacological Characteristics of Antivirals for Influenza
Zanamivir
ANTI-HEPATITIS VIRUS AGENTS
Drugs Used Mainly for Hepatitis C Virus Infection
Interferons
Figure 58-5. Interferon-Mediated Antiviral Activity Occurs via Multiple Mechanisms. The binding of IFN to specific cell surface receptor molecules signals the cell to produce a series of antiviral proteins. The stages of viral replication that are inhibited by various IFN-induced antiviral proteins are shown. Most of these act to inhibit the translation of viral proteins (mechanism 2), but other steps in viral replication also are affected (mechanisms 1, 3, and 4). The roles of these mechanisms in the other actions of IFNs are under study. Key: IFN = interferon; mRNA = messenger RNA; Mx = IFN-induced cellular protein with anti-viral activity; tRNA = transfer RNA; RNase L = latent cellular endoribonuclease; 2′5′A = 2′-5′-oligoadenylates; eIF-2α = protein synthesis initiation factor. (Modified from Baron et al., 1992, with permission.)
Ribavirin
Figure 58-6. Chemical Structures of the Anti-Hepatitis Drugs.
Drugs for Hepatitis B Virus Infection
Adefovir
Entecavir
Lamivudine
Telbivudine
Tenofovir
Clevudine
OTHER AGENTS
Imiquimod
BIBLIOGRAPHY
chapter 59 Antiretroviral Agents and Treatment of HIV Infection
I. Overview of HIV Infection and its Treatment
PATHOGENESIS OF HIV-RELATED DISEASE
Figure 59-1. Replicative cycle of HIV-1 showing the sites of action of available antiretroviral agents. Available antiretroviral agents are shown in blue. Key: RT, reverse transcriptase; cDNA, complementary DNA; mRNA, messenger RNA; RNase H, ribonuclease H; gp120 + gp41, extracellular and intracellular domains, respectively, of envelope glycoprotein. (Adapted from Hirsch and D'Aquila, 1993.)
Table 59-1 Antiretroviral Agents Approved for Use in the U.S.
PRINCIPLES OF HIV CHEMOTHERAPY
II.Drugs Used to Treat HIV Infection
NUCLEOSIDE AND NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS
Figure 59-2. Structures and mechanism of nucleoside and nucleotide reverse transcriptase inhibitors.
Table 59-2 Pharmacokinetic Properties of Nucleoside Reverse Transcriptase Inhibitorsa
Figure 59-3. Intracellular activation of nucleoside analog reverse transcriptase inhibitors. Drugs and phosphorylated anabolites are abbreviated; the enzymes responsible for each conversion are spelled out. The active antiretroviral anabolite for each drug is shown in the blue box. Key: ZDV, zidovudine; d4T, stavudine; ddC, dideoxycytidine; FTC, emtricitabine; 3TC, lamivudine; ABC, abacavir; ddI, didanosine; DF, disoproxil fumarate; MP, monophosphate; DP, diphosphate; TP, triphosphate; AMP, adenosine mono phosphate; CMP, cytidine monophosphate; dCMP, deoxycytidine monophosphate; IMP, inosine 5′-monophosphate; PRPP, phosphoribosyl pyrophosphate; NDP, nucleoside diphosphate. (Adapted with permission from Khoo et al., 2002. Copyright © Elsevier.)
Zidovudine
Stavudine
Lamivudine
Abacavir
Tenofovir
Emtricitabine
Didanosine
Zalcitabine
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
Figure 59-4. Structures and mechanism of non-nucleoside reverse transcriptase inhibitors.
Table 59-3 Pharmacokinetic Properties of Non-nucleoside Reverse Transcriptase Inhibitorsa
Nevirapine
Efavirenz
Etravirine
Delavirdine
HIV PROTEASE INHIBITORS
Figure 59-5. Mechanism of action of an HIV protease inhibitor. Shown here is a phenylalanine-proline target peptide sequence (in blue) for the protease enzyme (in golden brown) with chemical structures of the native amino acids (in lower box) to emphasize homology of their structures to that of saquinavir (at top).
Table 59-4 Pharmacokinetic Properties of HIV-1 Protease Inhibitorsa
Saquinavir
Ritonavir
Figure 59-6. Structure of available HIV protease inhibitors.
Fosamprenavir
Lopinavir
Atazanavir
Darunavir
Indinavir
Nelfinavir
Tipranavir
ENTRY INHIBITORS
Maraviroc
Figure 59-7. Mechanism of action of the HIV entry inhibitor maraviroc
Enfuvirtide
Figure 59-8. Mechanism of action of the HIV integrase inhibitor raltegravir.
INTEGRASE INHIBITORS
Raltegravir
CLINICAL SUMMARY
BIBLIOGRAPHY
Section VIII Chemotherapy of Neoplastic Diseases
chapter 60 General Principles of Cancer Chemotherapy
Table 60-1 Alkylating Agents
Table 60-2 Antimetabolites
Table 60-3 Natural Products
Table 60-4 Hormones and Antagonists
Table 60-5 Miscellaneous Agents
Figure 60-1. Summary of the mechanisms and sites of action of some chemotherapeutic agents useful in neoplastic disease.
Figure 60-2. Cell cycle specificity of antineoplastic agents.
BIBLIOGRAPHY
chapter 61 Cytotoxic Agents
I. Alkylating Agents and Platinum Coordination Complexes
Figure 61-1. Mechanism of action of alkylating agents.A. Activation reaction. B. Alkylation of N7 of guanine.
Figure 61-2. Nitrogen mustards employed in therapy.
Figure 61-3. Metabolism of cyclophosphamide.
Figure 61-4. Degradation of carmustine (BCNU) with generation of alkylating and carbamylating intermediates.
Pharmacological Actions
TOXICITIES OF ALKYLATING AGENTS
Bone Marrow Toxicity
Mucosal Toxicity
Neurotoxicity
Table 61-1 Dose-Limiting Extramedullary Toxicities of Single Alkylating Agents
CLINICAL PHARMACOLOGY
Nitrogen Mustards
Cyclophosphamide
MISCELLANEOUS ALKYLATING DRUGS
Ethyleneimines and Methylmelamines
Altretamine
Thiotepa
Alkyl Sulfonates
Nitrosoureas
Triazenes
Methylhydrazines
PLATINUM COORDINATION COMPLEXES
Cisplatin
Carboplatin
Oxaliplatin
II. Antimetabolites
FOLIC ACID ANALOGS
Figure 61-5. Sites of action of methotrexate and its polyglutamates. AICAR, aminoimidazole carboxamide; TMP, thymidine monophosphate; dUMP, deoxyuridine monophosphate; FH2Glun, dihydrofolate polyglutamate; FH4Glun, tetrahydrofolate polyglutamate; GAR, glycinamide ribonucleotide; IMP, inosine monophosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate.
Figure 61-6. Structures of folic acid and anti-folates. The shading identifies common structural features and areas of modification.
PYRIMIDINE ANALOGS
Figure 61-7. Structural modification of base and deoxyribonucleoside analogs. The yellow ellipses indicate sites modified to create antimetabolites. The specific substitutions are indicated in red for each drug. Modifications occur in the base ring systems, in their amino or hydroxyl side groups, and in the deoxyribose sugar found in deoxyribonucleosides.
Fluorouracil, Capecitabine, and Floxuridine (Fluorodeoxyuridine)
Figure 61-8. Structures of available pyrimidine analogs.
Figure 61-9. Activation pathways for 5-fluorouracil (5-FU) and 5-floxuridine (FUR). FUDP, floxuridine diphosphate; FUMP, floxuridine monophosphate; FUTP, floxuridine triphosphate; FUdR, fluorodeoxyuridine; FdUDP, fluorodeoxyuridine diphosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUTP, fluorodeoxyuridine triphosphate; PRPP, 5-phosphoribosyl-1-pyrophosphate.
Figure 61-10. Site of action of 5-fluoro-2′-deoxyuridine-5′-phosphate (5-FdUMP). 5-FU, 5-fluorouracil; dUMP, deoxyuridine monophosphate; TMP, thymidine monophosphate; TTP, thymidine triphosphate; FdUMP, fluorodeoxyuridine monophosphate; FH2Glun, dihydrofolate polyglutamate; FH4Glun, tetrahydrofolate polyglutamate.
Therapeutic Uses
CYTIDINE ANALOGS
Cytarabine (Cytosine Arabinoside; Ara-C)
Azacitidine (5-Azacytidine)
Gemcitabine
PURINE ANALOGS
Figure 61-11. Structural formulas of adenosine and various purine analogs.
6-Thiopurine Analogs
Fludarabine Phosphate
Cladribine
Clofarabine (2-Chloro-2′-Fluoro-Arabinosyladenine)
Nelarabine (6-Methoxy-Arabinosyl-Guanine)
Pentostatin (2′-Deoxycoformycin)
III. Natural Products
MICROTUBULE-DAMAGING AGENTS
VINCA ALKALOIDS
Vinblastine
Vincristine
Vinorelbine
TAXANES
Figure 61-12. Chemical structures of paclitaxel and its more potent analog, docetaxel.
ESTRAMUSTINE
EPOTHILONES
CAMPTOTHECIN ANALOGS
Figure 61-13. Chemical structures of camptothecin and its analogs.
Absorption, Fate, and Excretion
Terapeutic Uses
Clinical Toxicities
ANTIBIOTICS
Dactinomycin (Actinomycin D)
Athracyclines and Anthracenediones
Therapeutic Use
Doxorubicin
Epirubicin (ellence, others)
Valrubicin (valstar)
Mitoxantrone
EPIPODOPHYLLOTOXINS
Etoposide
Teniposide
DRUGS OF DIVERSE MECHANISM OF ACTION
Bleomycin
Figure 61-14. Chemical structures of bleomycin A2 and B2.
Mitomycin
Mitotane
Trabectedin
ENZYMES
l-Asparaginase
HYDROXYUREA
DIFFERENTIATING AGENTS
Retinoids
Arsenic Trioxide (ATO)
Histone Deacetylase Inhibitors
Figure 61-15. Chemical structures of vorinostat (A), and its metabolites, vorinostat O-glucuronide (B) and 4-anilino-4-oxobutanoic acid (C).
BIBLIOGRAPHY
chapter 62 Targeted Therapies: Tyrosine Kinase Inhibitors, Monoclonal Antibodies, and Cytokines
PROTEIN TYROSINE KINASE INHIBITORS
Inhibitors of the BCR-ABL Kinase: Imatinib, Dasatinib, and Nilotinib
Figure 62-1. The relative frequency of BCR-ABL kinase domain mutations detected at 31 different positions in clinical specimens from 245 patients in whom mutations were detected (219 with chronic myelocytic leukemia and 26 with Ph+ acute lymphoblastic leukemia). (Reproduced with permission from Hughes et al., 2006. Copyright © 2006 American Society of Hematology. Copyright restrictions may apply.)
Pharmacokinetics
EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS
Gefitinib
Figure 62-2. Growth factor signaling. Binding of agonist ligands to growth factor receptors causes receptor dimerization and activation of cytosolic protein kinase domains, leading to activation of multiple signaling pathways. Shown here are the RAS/MAPK/ERK, PI3K, and SMAD pathways, each of which is activated by receptors or cross-talk from adjacent pathways. Their signals regulate proliferation, metabolism, survival, and the synthesis of other growth factors, such as the vascular endothelial growth factor (VEGF).
Erlotinib
Resistance to Gefitinib and Erlotinib
Cetuximab
Therapeutic Uses
Panitumumab
HER2/neu Inhibitors
INHIBITORS OF ANGIOGENESIS
THALIDOMIDE
Figure 62-3. Schematic overview of proposed mechanisms of antimyeloma activity of thalidomide and its derivatives. Some biological hallmarks of the malignant phenotype are indicated in light-blue boxes. The proposed sites of action for thalidomide (letters inside red and green circles) are hypothesized to also be operative for thalidomide derivatives. A. Direct anti-multiple myeloma (MM) effect on tumor cells, including G1 growth arrest and/or apoptosis, even against MM cells resistant to conventional therapy. This is due to the disruption of the anti-apoptotic effect of BCL-2 family members, blocking NF-κB signaling, and inhibition of the production of interleukin-6 (IL-6). B. Inhibition of MM-cell adhesion to bone marrow stromal cells partially due to the reduction of IL-6 release. C. Decreased angiogenesis due to the inhibition of cytokine and growth factor production and release. D. Enhanced T-cell production of cytokines, such as IL-2 and interferon-γ (IFN-γ), that increase the number and cytotoxic functionality of natural killer (NK) cells. VEGF, vascular endothelial growth factor.
Thalidomide
Adverse Effects of Thalidomide and Lenalidomide
PROTEASOME INHIBITION: BORTEZOMIB
mTOR INHIBITORS: RAPAMYCIN ANALOGS
Figure 62-4. Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase (TK) growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. The various downstream outputs of the two complexes are shown. Phosphorylation of 4EBP by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism. 4EBP, eukaryotic initiation factor 4e (eif-4E) binding protein; S6K1, S6 kinase 1; FKBP12, the immunophilin target (binding protein) for tacrolimus (FK506).
BIOLOGICAL RESPONSE MODIFIERS
Monoclonal Antibodies
Unarmed Monoclonal Antibodies
Table 62-1 Monoclonal Antibodies Approved for Hematopoietic and Solid Tumors
Table 62-2 Dose and Toxicity of Monoclonal Antibody-Based Drugs
Monoclonal Antibody-Cytotoxic Conjugates
Radioimmunoconjugates
Interleukin-2
Colony-Stimulating Factors
BIBLIOGRAPHY
chapter 63 Natural Products in Cancer Chemotherapy: Hormones and Related Agents
GLUCOCORTICOIDS
PROGESTINS
ESTROGENS AND ANDROGENS
Estrogens and Androgens in the Treatment of Mammary Carcinoma
Anti-Estrogen Therapy
Table 63-1 Clinical Uses for Anti-Estrogen Therapy in ER+ Breast Cancer
Figure 63-1. Tamoxifen and its metabolites
Selective Estrogen Receptor Downregulators
Figure 63-2. Chemical structures of toremifene and fulvestrant.
Figure 63-3. Structure of the main aromatase inhibitors and the natural substrate androstenedione.
AROMATASE INHIBITORS
Figure 63-4. Steroid synthesis pathways. The enclosed area contains the pathways used by the adrenal glands and gonads. Enzymes are labeled in green, inhibitors in red. 11β: 11β-hydroxylase; 17,20: C-17,20-lyase (also CYP17); 17α: 17α-hydroxylase (CYP17); 17βR: 17β-reductase; 18: aldosterone synthase; 21: 21-hydroxylase; 3β: 3β-hydroxysteroid dehydrogenase; 5αR: 5α-reductase; A: aromatase.
Third-Generation Aromatase Inhibitors
HORMONE THERAPY IN PROSTATE CANCER
Gonadotropin-Releasing Hormone Agonists and Antagonists
Anti-Androgens
Table 63-2 Structures of GnRH and Decapeptide GnRH Analogs
Figure 63-5. Anti-androgens.
BIBLIOGRAPHY
Section IX Special Systems Pharmacology
chapter 64 Ocular Pharmacology
OVERVIEW OF OCULAR ANATOMY, PHYSIOLOGY, AND BIOCHEMISTRY
Extraocular Structures
Figure 64-1. Anatomy of the globe in relationship to the orbit and eyelids. Various routes of administration of anesthesia are demonstrated by the blue needle pathways.
Ocular Structures
Figure 64-2. Anatomy of the lacrimal system.
Anterior Segment
Table 64-1 Autonomic Pharmacology of the Eye and Related Structures
Figure 64-3. A. Anatomy of the eye. B. Enlargement of the anterior segment, revealing the cornea, angle structures, lens, and ciliary body. (Adapted with permission from Riordan-Eva P. Anatomy and embryology of the eye. In, Vaughan & Asbury's General Ophthalmology, 17th ed. (Riordan-Eva P, Whitcher JP, eds.) McGraw-Hill, New York, 2008. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.)
Figure 64-4. Autonomic innervation of the eye by the sympathetic (a) and parasympathetic (b) nervous systems. (Adapted with permission from Wybar KC, Kerr-Muir M. Bailliere's Concise Medical Textbooks, Ophthalmology, 3rd ed. Bailliere Tindall, New York, 1984. Copyright © Elsevier.)
Table 64-2 Effects of Pharmacological Agents on the Pupil
Figure 64-5. Anisocoria evaluation flowsheet. (Adapted with permission from Thompson and Pilley, 1976. Copyright © Elsevier.)
Table 64-3 Some Characteristics of Ocular Routes of Drug Administration
PHARMACOKINETICS AND TOXICOLOGY OF OCULAR THERAPEUTIC AGENTS
Drug-Delivery Strategies
Pharmacokinetics
Figure 64-6. Possible absorption pathways of an ophthalmic drug following topical application to the eye. Solid black arrows represent the corneal route; dashed blue arrows represent the conjunctival/scleral route; the black dashed arrow represents the nasolacrimal absorption pathway. (Adapted with permission from Chien et al, 1990. Copyright © Taylor & Francis Group, http://www.informaworld.com.)
THERAPEUTIC AND DIAGNOSTIC APPLICATIONS OF DRUGS IN OPHTHALMOLOGY
Chemotherapy of Microbial Diseases in the Eye
Antibacterial Agents
Table 64-4 Topical Antibacterial Agents Commercially Available for Ophthalmic Use
Antiviral Agents
Table 64-5 Antiviral Agents for Ophthalmic Use
Antifungal Agents
Antiprotozoal Agents
Table 64-6 Antifungal Agents for Ophthalmic Use
Use of Autonomic Agents in the Eye
Table 64-7 Autonomic Drugs for Ophthalmic Use
Use of Immunomodulatory and Antimitotic Drugs for Ophthalmic Therapy
Nonsteroidal Anti-Inflammatory Agents
Immunosuppressive and Antimitotic Agents
Drugs and Biological Agents Used in Ophthalmic Surgery
Table 64-8 Vitreous Substitutesa
Agents Used to Assist in Ocular Diagnosis
Agents Used to Treat Retinal Neovascularization and Macular Degeneration
Use of Anesthetics in Ophthalmic Procedures
Other Agents for Ophthalmic Therapy
Vitamins and Trace Elements
Table 64-9 Ophthalmic Effects of Selected Vitamin Deficiencies and Zinc Deficiency
Figure 64-7. A. Structural formula for β-carotene. B. Structural formulas for the vitamin A family of retinoids.
Figure 64-8. Major steps in photoreceptor signaling. In dark-adapted rod photoreceptors (left side of diagram), cytoplasmic cyclic GMP (green circles) and Ca2+ concentrations are high, and some of the cyclic GMP-gated cation channels in the plasma membrane (purple tetramer) are fully liganded and in the open state. Upon absorption of a photon by rhodopsin (R, red integral disk membrane protein), isomerization of the 11-cis retinal chromophore occurs to activate the receptor (R*). This leads to binding of transducin (T, pie-shaped heterotrimer) to R*, guanine nucleotide exchange of GDP (gray circle) for GTP (red circle), and formation of the activated transducin α subunit with bound GTP (Tα*). The Tα* species then binds phosphodiesterase 6 (PDE6) holoenzyme (P, blue αβ catalytic dimer with red γ subunits), causing de-inhibition by the ? subunit (Tα*-P*) and a large acceleration of catalysis of cyclic GMP to 5′-GMP at the active site (green arrow).The light-induced drop in cyclic GMP concentration (right side of diagram) causes the ligand-gated ion channel to close, causing membrane hyperpolarization. Ongoing extrusion of calcium by the Na+-Ca2+/K+ exchanger in the absence of Ca2+ influx through the channel also causes [Ca2+]i to decline, which is vital for the recovery process. DK, dark state; LT, light-activated state. (Reproduced with permission from Zhang X, Cote RH. cGMP signaling in vertebrate retinal photoreceptor cells. Front Biosci, 2005, 10:1191–1204.)
Wetting Agents and Tear Substitutes
Osmotic Agents
BIBLIOGRAPHY
chapter 65 Dermatological Pharmacology
Figure 65-1. Cutaneous drug delivery. Diagrammatic representation of the three compartments of the skin as they relate to drug delivery: surface, stratum (Str.), and viable tissues. After application of drugs to the surface, evaporation, structural, and compositional alterations, which determine the bioavailability of drugs, occur in the applied formulation. The stratum corneum limits diffusion of compounds into the viable skin and body. After absorption, compounds either bind targets in viable tissues or diffuse within the viable tissue or into the cutaneous vasculature, where they may be carried to internal cells and organs. (Reproduced with permission from Wolff et al., 2008. Figure 215-1. Copyright © The McGraw-Hill Companies, Inc. All rights reserved. Available at http://www.accessmedicine.com.)
Figure 65-2. Structure of the epidermis. The epidermis matures progressively from the stratum basale (SB) to the stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC). Important structural and metabolic proteins are produced at specific layers of the epidermis. (Reproduced with permission from Wolff et al., 2008. Figure 45-2. Copyright © The McGraw-Hill Companies, Inc. All rights reserved. Available at http://www.accessmedicine.com.)
Table 65-1 Important Considerations When a Drug Is Applied to the Skin
GLUCOCORTICOIDS
Topical Glucocorticoids
Table 65-2 Vehicles for Topically Applied Drugs
Table 65-3 Potency of Selected Topical Glucocorticoids
Systemic Glucocorticoids
RETINOIDS
Topical Retinoids
Table 65-4 Topical Retinoids
Tretinoin
Adapalene
Tazarotene
Alitretinoin
Bexarotene
Table 65-5 Systemic Retinoids
Systemic Retinoids
Isotretinoin
Acitretin
Bexarotene
VITAMIN ANALOGS
PHOTOCHEMOTHERAPY
Table 65-6 Photochemotherapy Methods
ANTIHISTAMINES
Figure 65-3. Heme biosynthesis pathway. A. Under physiological conditions, heme inhibits the enzyme δ aminolevulinic acid (δALA) synthetase by negative feedback. However, δ when ALA is provided exogenously, this control point is bypassed, leading to excessive accumulation of heme. B. Heme.
Table 65-7 Half-Life of Antihistamines
Table 65-8 Recommended Cutaneous Antifungal Therapy
ANTIMICROBIAL AGENTS
Antibiotics
Antifungal Agents
Antiviral Agents
Agents Used to Treat Infestations
ANTIMALARIAL AGENTS
CYTOTOXIC AND IMMUNOSUPPRESSIVE DRUGS
Antimetabolites
Table 65-9 Mechanism of Action for Selected Cytotoxic and Immunosuppressive Drugs
Alkylating Agents
Calcineurin Inhibitors
OTHER IMMUNOSUPPRESSIVE AND ANTI-INFLAMMATORY AGENTS
BIOLOGICAL AGENTS
T-cell Activation Inhibitors
Table 65-10 Biological Agents Commonly Used in Dermatology
Tumor Necrosis Factor Inhibitors
Figure 65-4. Immunopathogenesis of psoriasis. Psoriasis is a prototypical inflammatory skin disorder in which specific T-cell populations are stimulated by as-yet undefined antigen(s) presented by antigen-presenting cells. The T cells release pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), that induce keratinocyte and endothelial cell proliferation. APC, antigen-presenting cell; CLA, cutaneous lymphocyte-associated antigen.
Figure 65-5. Mechanisms of action of selected biological agents in psoriasis. Newer biological agents can interfere with one or more steps in the pathogenesis of psoriasis, resulting in clinical improvement. See text for details. ICAM-1, intercellular adhesion molecule 1; LFA, lymphocyte function-associated antigen; MHC, major histocompatibility complex; TCR, T-cell receptor.
Cutaneous T-cell Lymphoma
INTRAVENOUS IMMUNOGLOBULIN IN DERMATOLOGY
SUNSCREENS
Table 65-11 Agents Used for the Treatment of Pruritus
THE TREATMENT OF PRURITUS
DRUGS FOR HYPERKERATOTIC DISORDERS
DRUGS FOR ANDROGENETIC ALOPECIA
TREATMENT OF HYPERPIGMENTATION
MISCELLANEOUS AGENTS
BIBLIOGRAPHY
chapter 66 Contraception and Pharmacotherapy of Obstetrical and Gynecological Disorders
CONTRACEPTION
Planned Contraception
Table 66-1 One-Year Failure Rate with Various Forms of Contraception
Table 66-2 Brand Names and Formulations of Oral Contraceptives
Postcoital Contraception
Pregnancy Termination
DRUG THERAPY IN GYNECOLOGY
Induction of Sexual Maturation
Menopause
Table 66-3 Brand Names and Formulations of Agents Used for Hormone Replacemnt Therapy
Endometriosis
Hirsutism
Infections of the Female Reproductive Tract
Fertility Induction
Table 66-4 Sexually Transmitted Gynecological Infections and Recommended Therapies
Figure 66-1. Schematic diagram of idealized regimens using exogenous gonadotropins for fertility induction. A. Step-up regimen for ovulation induction. After menses, daily injections of gonadotropin (75 IU) are started. Follicle maturation is assessed by serial measurement of plasma estradiol and follicle size, as discussed in the text. If an inadequate response is seen, the dose of gonadotropin is increased to 112 or 150 IU/day. When one or two follicles have achieved a size of ≥17 mm in diameter, final follicle maturation and ovulation are induced by injection of human chorionic gonadotropin (hCG). Fertilization then is achieved at 36 hours after hCG injection by intercourse or intrauterine insemination (IUI). If more than two mature follicles are seen, the cycle is terminated and barrier contraception is used to avoid triplets or higher degrees of multifetal gestation. B. Long protocol for ovarian hyperstimulation using gonadotropin-releasing hormone (GnRH) agonist to inhibit premature ovulation, followed by in vitro fertilization (IVF). After the GnRH agonist has inhibited endogenous secretion of gonadotropins, therapy with exogenous gonadotropins is initiated. Follicle maturation is assessed by serial measurements of plasma estradiol and follicle size by ultrasonography. When three or more follicles are ≥17 mm in diameter, then ovulation is induced by injection of hCG. At 32–36 hours after the hCG injection, the eggs are retrieved and used for IVF. Exogenous progesterone is provided to promote a receptive endometrium, followed by embryo transfer at 3–5 days after fertilization. C. Protocol for ovarian hyperstimulation in an IVF protocol using a GnRH antagonist. The cycle duration is shorter because the GnRH antagonist does not induce a transient flare of gonadotropin secretion that might disrupt the timing of the cycle, but many other elements of the cycle are analogous to those in B. IU, intrauterine.
DRUG THERAPY IN OBSTETRICS
General Principles of Drug Therapy of Pregnant Women
Table 66-5 FDA Use-in-Pregnancy Ratings
Pregnancy-Induced Hypertension/Pre-eclampsia
Prevention or Arrest of Preterm Labor
Figure 66-2. Sites of action of tocolytic drugs in the uterine myometrium. The elevation of cellular Ca2+ promotes contraction via the Ca2+/calmodulin-dependent activation of myosin light chain kinase (MLCK). Relaxation is promoted by the elevation of cyclic nucleotides (cAMP and cGMP) and their activation of protein kinases, which cause phosphorylation/inactivation of MLCK. Pharmacological manipulations to reduce myometrial contraction include: • inhibiting Ca2+ entry (Ca2+ channel blockers, Mg2SO4)• reducing mobilization of intracellular Ca2+ by antagonizing GPCR-mediated activation of the Gq-PLC-IP3-Ca2+ pathway (with antagonists of the FP and OXT receptors) or reducing production of the FP agonist, PGF2α (with COX inhibitors)• enhancing relaxation by elevating cellular cyclic AMP (with β2 adrenergic agonists that activate Gs-AC) and cyclic GMP (with NO donors that stimulate soluble guanylyl cyclase) sGC, soluble guanylyl cyclase; AC, adenylyl cyclase; FP, the PGF2α receptor; OXT, the oxytocin receptor; PLC, phospholipase C; COX, cyclooxygenase.
Initiation of Labor
Prevention/Treatment of Postpartum Hemorrhage
BIBLIOGRAPHY
chapter 67 Environmental Toxicology: Carcinogens and Heavy Metals
ENVIRONMENTAL RISK ASSESSMENT AND RISK MANAGEMENT
Epidemiological Approaches to Risk Assessment
Toxicological Approaches to Risk Assessment
Figure 67-1. LOAEL and NOAEL. The theoretical dose-response curve from an animal study demonstrates the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL). Below the NOAEL level, there is considerable uncertainty as to the shape of the response curve. It could continue linearly to reach a threshold dose (T) where there would be no harmful effects from the toxicant, or it could have a number of different possible inflection points. Each of these curves would have very different impacts on human populations. *Statistically significant.
Integrated Risk Assessment and Risk Management
Interventions for Environmental Exposure: Pharmacology and Prevention
CARCINOGENS AND CHEMOPREVENTION
Carcinogenesis
Table 67-1 Examples of Important Carcinogensa
Figure 67-2. Carcinogenesis: initiation and promotion. There are many steps that occur between the exposure to a genotoxic carcinogen and the development of cancer. Processes in red lead to the development of cancer, while those in green reduce the risk. Non-genotoxic carcinogens act by enhancing steps leading to cancer and/or inhibiting protective processes. A chemopreventive agent acts by inhibiting steps leading to cancer or by increasing protective processes.
Chemoprevention
Table 67-2 Chemopreventive Agents Being Studied in Humans
Figure 67-3. Metabolism and actions of aflatoxin B1. Following absorption, aflatoxin B1 undergoes activation by CYPs to its 8,9-epoxide, which can be detoxified by glutathione S-transferases (GSTs) or by spontaneous hydration. Alternatively, it can react with cellular macromolecules such as DNA and protein, leading to toxicity and cancer. Oltipraz, green tea polyphenols (GTPs), and isothiocyanates (ITCs) decrease aflatoxin carcinogenesis by inhibiting the CYPs involved in activating aflatoxin and increasing the synthesis of the cofactor GSH for GSTs involved in detoxification.
METALS
Lead
Table 67-3 Toxic Metals with Frequent Environmental or Occupational Exposurea
Figure 67-4. Heme biosynthesis and actions of lead. Lead interferes with the biosynthesis of heme at several enzymatic steps. Steps that definitely are inhibited by lead are indicated by red blocks. Steps at which lead is thought to act but where evidence is inconclusive are indicated by pink blocks.
Figure 67-5. Manifestations of lead toxicity associated with varying concentrations of lead in the blood of children and adults. δ-ALA, δ-aminolevulinate.
Mercury
Figure 67-6. Mobilization of mercury in the environment. Metallic mercury (Hg0) is vaporized from the Earth's surface both naturally and through human activities such as burning coal. In the atmosphere, Hg0 is oxidized to form divalent inorganic mercury (Hg2+). Hg2+ then falls to the surface in rain. Aquatic bacteria can methylate Hg2+ to form methyl mercury (MeHg+). MeHg+ in plankton is consumed by fish. Because of its lipophilicity, MeHg+ bioaccumulates up the food chain.
Figure 67-7. The concentration of mercury vapor in the air and related concentrations of mercury in urine are associated with a variety of toxic effects.
Health Effects
Arsenic
Figure 67-8. Arsenic in drinking water. (A) World map demonstrating regions where there is increased arsenic exposure in drinking water. (B) Map of Bangladesh demonstrating arsenic concentrations in drinking water in samples from wells across the country. (Adapted from BGS and DPHE, 2001. This report was produced by the British Geological Survey and the Department of Public Health Engineering (Bangladesh) undertaking a project funded by the UK Department for International Development.)
Figure 67-9. Metabolism of arsenic. GSH, reduced glutathione; GSSG, oxidized glutathione; SAM, S-adenosyl-l-methionine; SAH, S-adenosyl-l-homocysteine. AS3MT, arsenite methyltransferase; MMAV, monomethylarsonic acid; MMAIII, monomethylarsonous acid; DMAV, dimethyl arsinic acid.
Cadmium
Chromium
TREATMENT OF METAL EXPOSURE
Figure 67-10. Structures of chelators commonly used to treat acute metal intoxication. CaNa2EDTA, calcium disodium ethylenediamine tetraacetic acid; DMPS, sodium 2,3-dimercaptopropane sulfonate.
Ethylenediaminetetraacetic Acid (EDTA)
Dimercaprol
Succimer
Sodium 2,3-Dimercaptopropane Sulfonate (DMPS)
Penicillamine; Trientine
Deferoxamine; Deferasirox
BIBLIOGRAPHY
Back Matter
Appendix I Principles of Prescription Order Writing and Patient Compliance
THE MECHANICS OF PRESCRIPTION ORDER WRITING
History
Current Practice
Figure AI-1. The prescription. The prescription must be carefully prepared to identify the patient and the medication to be dispensed, as well as the manner in which the drug is to be administered. Accuracy and legibility are essential. Use of abbreviations, particularly Latin, is discouraged, because it leads to dispensing errors. Inclusion of the therapeutic purpose in the subscription (e.g., "for control of blood pressure") can prevent errors in dispensing. For example, the use of losartan for the treatment of hypertension may require 100 mg/day (1.4 mg/kg/day), whereas treatment of congestive heart failure with this angiotensin II receptor antagonist generally should not exceed 50 mg/day. Including the therapeutic purpose of the prescription also can assist patients in organizing and understanding their medications. In addition, including the patient's weight on the prescription can be useful in avoiding dosing errors, particularly when drugs are administered to children.
Prescriptive Authority
Avoiding Confusion
Proper Patient Information
Proper Use of Prescription Pad
Table AI-1 Controlled Substance Schedules
Choice and Amount of Drug Product Dispensed
The Prescription as a Commodity
Prescription Drug Advertising
ERRORS IN DRUG ORDERS
CONTROLLED SUBSTANCES
Prescription Orders for Controlled Substances
Execution of the Order
Oral Orders
Refills
Preventing Diversion
DRUG STANDARDS AND CLASSIFICATION
COMPLIANCE
Table AI-2 Suggestions for Improving Patient Compliance
The Patient-Provider Relationship
Patients and Their Beliefs
The Therapy
ELECTRONIC PRESCRIBING
REFERENCES
Appendix II Design and Optimization of Dosage Regimens: Pharmacokinetic Data
TABULATED PHARMACOKINETIC PARAMETERS
ALTERATIONS OF PARAMETERS IN THE INDIVIDUAL PATIENT
(Equation A-1)
(Equation A-2)
(Equation A-3)
(Equation A-4)
INDIVIDUALIZATION OF DOSAGE
Table AII-1 Pharmacokinetic Data
Index