DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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transporter. The 5-HT transporter (SERT [SLC6A4]) is localized inthe membrane of serotonergic axon terminals (where it terminatesthe action of 5-HT in the synapse) and in the membrane of platelets(where it takes up 5-HT from the blood). This uptake system is themeans by which platelets acquire 5-HT, since they lack the enzymesrequired for 5-HT synthesis. The 5-HT transporter and othermonoamine transporters have been cloned (Chapters 5, 8, and 12).The amine transporters are distinct from VMAT2, which concentratesamines in intracellular storage vesicles and is a nonspecificamine carrier, whereas the 5-HT transporter is specific. The 5-HTtransporter is regulated by phosphorylation and subsequent internalization(for a review, see Steiner et al., 2008), providing a mechanismfor dynamic regulation of serotonergic transmission.The principal route of metabolism of 5-HTinvolves oxidative deamination by monoamine oxidase(MAO); the aldehyde intermediate thus formed isconverted to 5-hydroxyindole acetic acid (5-HIAA)by aldehyde dehydrogenase (Figure 13–2). An alternativeroute, reduction of the acetaldehyde to an alcohol,5-hydroxytryptophol, is normally insignificant.5-HIAA is actively transported out of the brain by aprocess that is sensitive to the nonspecific transportinhibitor, probenecid.Since 5-HIAA formation accounts for nearly 100% of themetabolism of 5-HT in brain, the turnover rate of brain 5-HT isestimated by measuring the ratio of 5-HIAA/5-HT. 5-HIAA frombrain and peripheral sites of 5-HT storage and metabolism is excretedin the urine along with small amounts of 5-hydroxytryptophol sulfateor glucuronide conjugates. The usual range of urinary excretionof 5-HIAA by a normal adult is 2-10 mg daily. Largeramounts are excreted by patients with malignant carcinoid, providinga reliable diagnostic test for the disease. Ingestion of ethanolresults in elevated amounts of NADH 2(Chapter 23), which diverts5-hydroxyindole acetaldehyde from the oxidative route to thereductive pathway (Figure 13–2) and tends to increase the excretionof 5-hydroxytryptophol and correspondingly reduce the excretionof 5-HIAA.Of the two isoforms of MAO (A and B) (see Chapter 8 andBortolato et al., 2008 for a review), MAO-A preferentially metabolizes5-HT and norepinephrine; clorgyline is a specific inhibitorof this enzyme. MAO-B prefers β-phenylethylamine and benzylamineas substrates; low-dose selegiline is a relatively selectiveinhibitor of MAO-B. Dopamine and tryptamine are metabolizedequally well by both isoforms. Neurons contain both isoforms ofMAO, localized primarily in the outer membrane of mitochondria.MAO-B is the principal isoform in platelets, which contain largeamounts of 5-HT.Other minor pathways of metabolism of 5-HT, such as sulfationand O- or N-methylation, have been suggested. The latterreaction could lead to formation of an endogenous psychotropic substance,5-hydroxy-N,N-dimethyltryptamine (bufotenine; Figure 13–1).However, other methylated indoleamines such as N,N-dimethyltryptamineand 5-methoxy-N,N-dimethyltryptamine are far moreactive hallucinogens and are more likely candidates to be endogenouspsychotomimetics.PHYSIOLOGICAL FUNCTIONSOF SEROTONINMultiple 5-HT ReceptorsBased on data from studies of 5-HT’s actions in peripheraltissues, researchers hypothesized that the multipleactions of 5-HT involved interaction with distinct 5-HTreceptor subtypes. Extensive pharmacological characterizationand the cloning of receptor cDNAs have confirmedthis hypothesis (Barnes and Sharp, 1999;Bockaert et al., 2006). The multiple 5-HT receptor subtypescloned comprise the largest known neurotransmitterreceptorfamily. The 5-HT receptor subtypes areexpressed in distinct but often overlapping patterns(Palacios et al., 1990) and are coupled to different transmembrane-signalingmechanisms (Table 13–1). Most5-HT receptors, especially the 5-HT 2Creceptor, canactivate G-proteins independently of agonists, a propertyknown as constitutive activity (Berg et al., 2008).Four of seven currently recognized 5-HT receptor familieshave defined functions (described later). The 5-HT 1,5-HT 2, and 5-HT 4–7receptor families are members ofthe superfamily of GPCRs (Chapter 3). The 5-HT 3receptor is a ligand-gated ion channel that gates Na +and K + and has a predicted membrane topology akin tothat of the nicotinic cholinergic receptor (Chapter 11).History of 5-HT Receptor Subtypes. In 1957, Gaddum and Picarelliproposed the existence of two 5-HT receptor subtypes, M and Dreceptors. M receptors were believed to be located on parasympatheticnerve endings, controlling the release of acetylcholine,whereas D receptors were thought to be located on smooth muscle.Subsequent studies in both the periphery and brain were consistentwith the notion of multiple subtypes of 5-HT receptors (for a review,see Sanders-Bush and Airey, 2008), now known to be members ofthe superfamilies of GPCRs and ligand-gated ion channel receptors.The current classification scheme (Hoyer et al., 1994) is based onpharmacological properties, second-messenger function, and deducedamino acid sequence, and includes seven subfamilies of 5-HT receptors(Table 13–1).The radioligand-binding studies of Peroutka and Snyder(1979) provided the first definitive evidence for two distinct recognitionsites for 5-HT. 5-HT 1receptors had a high affinity for [ 3 H]5-HT,while 5-HT 2receptors had a low affinity for [ 3 H]5-HT and a highaffinity for [ 3 H]spiperone. Subsequently, high affinity for 5-HT wasused as a primary criterion for classifying a receptor subtype as amember of the 5-HT 1receptor family. This classification strategyproved to be invalid; for example, a receptor expressed in the choroidplexus was named the 5-HT 1Creceptor because it was the thirdreceptor shown to have a high affinity for 5-HT. However, based onits pharmacological properties, second-messenger function, anddeduced amino acid sequence, the 5-HT 1Creceptor clearly belongedto the 5-HT 2receptor family and was subsequently renamed the 5-HT 2Creceptor. Evidence suggests that the 5-HT 1Dβreceptor is the human337CHAPTER 135-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE
Table 13–1Serotonin Receptor Subtypes5-HT 1 , 5-HT 2 , 5-HT 4–7STRUCTURAL FAMILIES5-HT 3G protein–coupled receptor5-HT–gated ion channelGENE SIGNAL SELECTIVE SELECTIVESUBTYPE STRUCTURE TRANSDUCTION LOCALIZATION FUNCTION AGONIST ANTAGONIST5-HT 1AIntronless b AC Raphe nuclei Autoreceptor 8-OH-DPAT WAY 100135CortexHippocampusa5-HT 1BIntronless b AC Subiculum Autoreceptor — —Globus pallidusSubstantia nigra5-HT 1DIntronless b AC Cranial blood vessels Vasoconstriction Sumatriptan —Globus pallidusSubstantia nigra5-HT 1EIntronless b AC Cortex — — —Striatumb5-HT 1FIntronless b AC Brain and periphery — — —5-HT 2AIntrons a PLC and Platelets Aggregation α-Methyl-5-HT, Ketanserin(D receptor) a PLA 2Smooth muscle Contraction DOI, MCPPCerebral cortex Neuronal excitation LY53857MDL 100, 9075-HT 2BIntrons a PLC Stomach fundus Contraction α-Methyl-5-HT, DOI LY53857SB2065535-HT 2CIntrons a PLC Choroid plexus CSF production α-Methyl-5-HT, LY53857a PLA 2Hypothalamus Neuronal excitation DOI, MK 2.2 SB 2022084Mesulergine5-HT 3Introns Ligand-operated Parasympathetic nerves Neuronal excitation 2-Methyl-5-HT Ondansetron(M receptor) ion channel Solitary tract TropisetronArea postrema5-HT 4Introns a AC Hippocampus Neuronal excitation Renzapride GR 113808GI tract5-HT 5AIntrons b AC Hippocampus Unknown — —5-HT 5BIntrons Unknown — Pseudogene — —5-HT 6Introns a AC Hippocampus Neuronal excitation — SB 271046StriatumNucleus accumbens5-HT 7Introns a AC Hypothalamus Unknown 5-carboxamino-HippocampustryptamineGI tractaAlso referred to as 5-HT 1DB. b Also referred to as 5-HT 1EB.AC, adenylyl cyclase; PLC, phospholipase C; PLA 2; phospholipase A 2; 8-OH-DPAT, 8-hydroxy-(2-N,N-dipropylamino)-tetraline; DOI, 1-(2,5-dimethoxy-4-iodophenyl) isopropylamine;MCPP, metachlorphenylpiperazine; MK212.
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viiiCONTENTS22. Treatment of Centra
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xiiCONTRIBUTORSBruce A. Chabner, MD
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xivCONTRIBUTORSJonathan M. Meyer, M
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xviCONTRIBUTORSRobert H. Tukey, PhD
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4SECTION IGENERAL PRINCIPLESbegan i
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6SECTION IGENERAL PRINCIPLESTARGETS
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its mission cannot possibly be acco
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10SECTION IGENERAL PRINCIPLESHMG-Co
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12SECTION IGENERAL PRINCIPLESit to
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14SECTION IGENERAL PRINCIPLESviolat
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16SECTION IGENERAL PRINCIPLESyears.
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18SECTION IGENERAL PRINCIPLESDRUGDO
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20SECTION IGENERAL PRINCIPLEScompou
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22SECTION IGENERAL PRINCIPLESgroups
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24SECTION IGENERAL PRINCIPLESphysic
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26SECTION IGENERAL PRINCIPLESdivers
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28SECTION IGENERAL PRINCIPLESphase
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30SECTION IGENERAL PRINCIPLESDivisi
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32SECTION IGENERAL PRINCIPLESconsis
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34SECTION IGENERAL PRINCIPLEStherap
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36SECTION IGENERAL PRINCIPLESMainte
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38SECTION IGENERAL PRINCIPLESThe ne
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42 signaling compounds are termed a
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44 receptors, but because the endog
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46 ligand-receptor complex, LR*. Th
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48 agonist plus an effective concen
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50SECTION IGENERAL PRINCIPLESPRESCR
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52 constrained by compartmentation
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54A. Activation by Ligand Binding o
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56 Second MessengersSECTION IGENERA
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58 markedly stimulates Ca 2+ flux,
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60 voltage-gated (Jegla et al., 200
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62SECTION IA(a) UnligandedreceptorI
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64 from the complex allowing the p5
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66 upon binding ligand. Other membe
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68 FADD/TRAF2, and caspase 8, which
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70 of cyclic GMP are also increased
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72 Vo NK, Gettemy JM, Coghlan VM. I
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74100ADeathSECTION I% of Population
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76SECTION IGENERAL PRINCIPLESisofor
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78SECTION IGENERAL PRINCIPLESantago
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80SECTION IGENERAL PRINCIPLESarrhyt
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82SECTION IGENERAL PRINCIPLESThe in
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84SECTION IGENERAL PRINCIPLESGastri
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86SECTION IGENERAL PRINCIPLESTable
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90TherapeuticeffectMetabolismTExcre
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92Clearance organs(liver, kidney)Co
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94Passive transport (downhill trans
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96SECTION IGENERAL PRINCIPLESNoncom
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Table 5-1Regulation of Transporter
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100ExtracellularSECTION IGENERAL PR
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Table 5-2Families in the Human Solu
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Table 5-3The ATP Binding Cassette (
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Table 5-4ABC Transporters Involved
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108SECTION IGENERAL PRINCIPLESIn th
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110SECTION IGENERAL PRINCIPLESthe u
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112SECTION IGENERAL PRINCIPLESOC +B
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114SECTION IGENERAL PRINCIPLEStrans
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116SECTION IGENERAL PRINCIPLESincre
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118SECTION IGENERAL PRINCIPLESHaseg
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120SECTION IGENERAL PRINCIPLESmulti
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124SECTION IGENERAL PRINCIPLESconst
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126SECTION IGENERAL PRINCIPLESorall
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Table 6-2Major Reactions Involved i
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130SECTION IGENERAL PRINCIPLESco-ad
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132SECTION IGENERAL PRINCIPLESreact
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134SECTION IGENERAL PRINCIPLESSN-38
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136SECTION IGENERAL PRINCIPLESnon-c
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Table 6-4Indications and Unwanted S
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140SECTION IGENERAL PRINCIPLESsyndr
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142SECTION IGENERAL PRINCIPLESthe t
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146SECTION IGENERAL PRINCIPLESstres
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148SECTION IGENERAL PRINCIPLESsubst
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150SECTION IGENERAL PRINCIPLESEthni
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152Monogenic traitMultigenic traitS
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154SECTION IGENERAL PRINCIPLESlikel
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15625060Common genetic formSECTION
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158AgeneCYP3A5*1 allele123456789101
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Table 7-3Examples of Genetic Polymo
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162warfarinCYP2C9hydroxywarfarin5SE
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164SECTION IGENERAL PRINCIPLESin a
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166SECTION IGENERAL PRINCIPLESBIBLI
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168SECTION IGENERAL PRINCIPLESRosne
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172 regulation of sacral parasympat
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174 third lumbar segment. The axons
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176 ganglia, the ratio of pregangli
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Table 8-1Responses of Effector Orga
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Table 8-1Responses of Effector Orga
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182 While these criteria are applic
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184 those vesicles in close proximi
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186HemicholiniumAcCoA + CholineChol
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188 in transmitter release comes fr
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190 Subtypes of Nicotinic Acetylcho
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Table 8-3Characteristics of Muscari
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194 and inhibition of excitable mem
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196SECTION IINEUROPHARMACOLOGYcorre
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Table 8-5Characteristics of Plasma
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200 by activation of β 2adrenergic
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202SECTION IIHOHOCH 3 OHOHOHHO H OH
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Table 8-6Characteristics for Adrene
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Table 8-7Representative Agents Acti
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208α 1A α 2A β 1NH 2NH 2NH 2SECT
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210 uncoupling of G-protein signali
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212 and atenolol, which antagonize
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214 to inhibit its own release. NPY
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216 Furchgott RF. Endothelium-deriv
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218 Nucleotides as Regulators of Ce
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220 M 1through M 5muscarinic recept
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222 difficult to observe with admin
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224 The difficulty in developing su
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226 neurotransmitter release, the p
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228 parasympathetic postganglionic
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230 sympathetic cholinergic fibers,
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Table 9-3Muscarinic Receptor Antago
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234 efficient, resulting in the del
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236 Chapple C, Khullar V, Gabriel Z
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240 In the 1950s, a series of aroma
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242 tertiary amine physostigmine ex
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Table 10-1Chemical Classification o
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246 The sites of action of anti- Ch
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248 tolerance reassessments, and re
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250 animals after long- term exposu
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252 When the diagnosis of myastheni
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254 Gallo MA, Lawryk NJ. Organic ph
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256 the inhibitory amino acids (γ-
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258 abundance in muscle, along with
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260 and the remainder of the muscle
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262SECTION IINEUROPHARMACOLOGYmyeli
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Table 11-2Classification of Neuromu
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266 Preventing Trauma During Electr
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268 reduced renal function (pancuro
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270 that are selective for M 1musca
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272 and its metabolites are elimina
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274 gastric emptying. Although the
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276 Volle RL. Nicotinic ganglion-st
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278Adrenergic AgonistsDirect-acting
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280SECTION IITable 12-1Chemical Str
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282 when both types of receptors ar
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284 falls (epinephrine reversal). A
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286 increase of 20-30% in oxygen co
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288 Therapeutic Uses and Status. NE
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290 may occur, particularly in pati
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Page 320 and 321: 294 agonist that has twice the pote
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Page 326 and 327: 300 treatment of attention-deficit/
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Page 330 and 331: 304 transient or may respond to adj
Page 332 and 333: 306Alkylating agentCH 3OCH 2 CHNCH
Page 334 and 335: 308 Syncopal episodes also have occ
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Page 338 and 339: 312OOOOHHNOOHHNOBISOPROLOLBETAXOLOL
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Page 349: 322SECTION IINEUROPHARMACOLOGYTable
Page 353: 324SECTION IINEUROPHARMACOLOGYTable
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Page 367: 336SECTION IINEUROPHARMACOLOGYNH 2N
Page 372 and 373: 340SECTION IINEUROPHARMACOLOGY5-HT
Page 374 and 375: Table 13-3Some Actions of 5-HT in t
Page 376 and 377: 344 suppressant in the management o
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Page 382 and 383: 350 mCPP, an active metabolite of t
Page 384 and 385: 352 Oby AADC, the same enzyme that
Page 386 and 387: 354ND1 receptor familyD2 receptor f
Page 388 and 389: 356SECTION IINEUROPHARMACOLOGYMesoc
Page 390 and 391: 358 receptor agonist and a weak D 1
Page 392 and 393: 360 Delgado PL, Charney DS, Price L
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Page 396 and 397: 364 system and integrate somatic an
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Page 400 and 401: 368A Ion channels α 1 subunits for
Page 402 and 403: Table 14-1Subtypes of Ca 2+ Channel
Page 404 and 405: 372SECTION IINEUROPHARMACOLOGYselec
Page 406 and 407: 374Presynapticneuron11 107Neurotran
Page 408 and 409: 376SECTION IINEUROPHARMACOLOGYParav
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Page 412 and 413: 380 (NMDA) receptors and non- NMDA
Page 414 and 415: Table 14-4Subtypes of Muscarinic Re
Page 416 and 417: 384 thence to adenylyl cyclase. α
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386HistamineNH 2HNNSECTION IIH 1 H
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388β-LPHSignal peptideJP ACTH γ-L
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390 Oglutamate (NMDA)-mediated neur
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392 (e.g., ethanol) can exert relat
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394 Bleich S, Romer K, Wiltfang J,
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398 disease, especially myocardial
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400SECTION IINEUROPHARMACOLOGYTable
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402Table 15-1Antidepressants: Chemi
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404SECTION IINEUROPHARMACOLOGYanoth
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408 antipsychotics are synergistic
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410MAO to monoaminergic nerve termi
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412SECTION IINEUROPHARMACOLOGYDrug
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414SECTION IINEUROPHARMACOLOGYreupt
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418 glutamate receptor. Advances in
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420SECTION IINEUROPHARMACOLOGYPRESY
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SECTION IINEUROPHARMACOLOGY422 Schi
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424Table 16-1SECTION IINEUROPHARMAC
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426Table 16-1Chemical Structures, D
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428SECTION IINEUROPHARMACOLOGYantip
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430SECTION IINEUROPHARMACOLOGYDA re
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436 Absorption for most agents is q
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438 seen, although they are less pr
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440 health of the patient. Weight g
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442 increased risk of sudden death
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444 supporting data for certain anx
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446 treatment with both Li + and va
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448 therapeutic range (6-12 μg/mL)
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450 Li + intoxication. Li + freely
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452 Barten DM, Albright CF. Therape
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454 Mahmoud RA, Pandina GJ, Turkoz
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458 searches for agents with more s
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460 by barbiturates and volatile an
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462 a model in which benzodiazepine
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Table 17-2Major Metabolic Relations
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468SECTION IINEUROPHARMACOLOGYincid
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Table 17-4Structures, Trade Names,
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472SECTION IINEUROPHARMACOLOGYAbuse
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474SECTION IINEUROPHARMACOLOGYenzym
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476 Controversy in the management o
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478 BIBLIOGRAPHYSECTION IINEUROPHAR
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480 Twyman RE, Rogers CJ, Macdonald
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482 the existence of three main rec
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Table 18-1Actions and Selectivities
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486SECTION IINEUROPHARMACOLOGYNocis
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488 the receptor selectivity of the
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490SECTION IINEUROPHARMACOLOGY(Sork
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492SECTION IINEUROPHARMACOLOGYPrefr
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494SECTION IINEUROPHARMACOLOGYindir
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496SECTION IINEUROPHARMACOLOGYreser
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500SECTION IINEUROPHARMACOLOGYaFigu
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502SECTION IINEUROPHARMACOLOGYreact
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504 may not do so with meperidine;
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506 The use of fentanyl and sufenta
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508 doses of 20-25 mg morphine give
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510 of psychotomimetic side effects
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512 syndrome in patients dependent
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Table 18-3Epidural or Intrathecal O
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516 significantly (Du Pen et al., 1
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Routes of Administration Available.
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question the accuracy of the diagno
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522 Burkle H, Dunbar S, Van Aken H.
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524 McIntosh M, Kane K, Parratt J.
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528 asthmaticus with halothane and
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Table 19-1Properties of Inhalationa
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532 two-pore domain channels (Patel
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534Table 19-2Pharmacological Proper
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536 suppression of the EEG (Todd et
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SECTION IINEUROPHARMACOLOGY538 Etom
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Table 19-3Some Pharmacological Effe
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542 and side-effect profiles. Halot
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544 response to reduced blood press
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546 nonflammable and non-explosive
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548 anesthesia (Rasmussen et al., 2
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550 few side effects. However, succ
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554 effects on different organ syst
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556 potential to promote absorption
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558 CNS. Hypercarbia depresses the
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560 of other gases, resulting in a
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562 Grounds RM, Maxwell DL, Taylor
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564 Taylor DR, Pijnenburg MW, Smith
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566H 3 CO O CH 3C NOOC O H 2 NC OC
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568Aβ 1 subunitα subunitNI II III
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Table 20-1Susceptibility to Block T
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572 such as methylparaben that may
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574 complicates evaluation of the n
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576 amount of cream that can be app
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578 successful application of spina
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580 intravascular injection easier
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582 Yarov-Yarovoy V, McPhee JC, Ids
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therapy. More detailed information
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586SECTION IINEUROPHARMACOLOGYFigur
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588OpenInactivatedNa + Na +vigabatr
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590 The cellular electrophysiologic
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Table 21-3Interactions of Anti-Seiz
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594 These effects have been observe
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596 Oxcarbazepine is a prodrug that
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598 displacement of phenytoin from
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600 explain lamotrigine’s actions
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602 Pharmacological Effects and Mec
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604 should not be taken lightly, be
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606 of women with epilepsy have bee
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610 excitotoxic injury, regional va
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612SECTION IIPRESYNAPTIC TERMINALDi
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Treatment of Parkinson DiseaseCommo
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616 Levodopa therapy can have a dra
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618 of levodopa/carbidopa. The acti
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620 year to AD (Petersen et al., 20
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622 potentially vagotonic propertie
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624 designated IT15. It encodes a p
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626Extrafusalmuscle fibersUppermoto
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628 therapy for advanced Parkinson
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630 (the “proof” of an alcoholi
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632 methanol is taken along with et
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634 2006). Acutely, ethanol results
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636 atherogenesis (Chapter 31). Ano
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638 pancreatitis has been known to
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640 may occur with patients who app
Page 691 and 692:
642 termed fetal alcohol effects (F
Page 693 and 694:
644 metabolites of the drug, especi
Page 695 and 696:
646 Lemoine P, Harousseau H, Bortey
Page 697 and 698:
Page 699 and 700:
650 an addiction. These variables c
Page 701 and 702:
652 paucity of other options for pl
Page 703 and 704:
654 Withdrawal signs and symptoms o
Page 705 and 706:
656SECTION IINEUROPHARMACOLOGYA sig
Page 707 and 708:
Page 709 and 710:
660 crosses the blood-brain barrier
Page 711 and 712:
662 high school students has declin
Page 713 and 714:
664 developed and tested in control
Page 715 and 716:
666 demonstrated in humans, the cer
Page 717 and 718:
668 Mason BJ. Acamprosate and naltr
Page 719 and 720:
Page 721 and 722:
672Glomerulus1111210139(Outer Strip
Page 723 and 724:
674CCCCCCCCCCCCCBB1convectivesolute
Page 725 and 726:
676 7. As water and solutes accumul
Page 727 and 728:
Table 25-1Excretory and Renal Hemod
Page 729 and 730:
680 However, even with a high degre
Page 731 and 732:
682 Effects on Urinary Excretion. O
Page 733 and 734:
684SECTION IIIMODULATION OF CARDIOV
Page 735 and 736:
686 cardiac arrhythmias, particular
Page 737 and 738:
Table 25-5Inhibitors of Na + -Cl -
Page 739 and 740:
Thiazide diuretics decrease blood p
Page 741 and 742:
692 Pentamidine and high-dose trime
Page 743 and 744:
694ALATE DISTAL TUBULEAND COLLECTIN
Page 745 and 746:
696 channels are expressed in IMCD.
Page 747 and 748:
6981DIURETICSNa+ExcretionRateMABPMA
Page 749 and 750:
700ChronicrenalfailureNephroticsynd
Page 751 and 752:
Page 753 and 754:
Page 755 and 756:
706AVPAVPV 2β γα sAdenylylCyclas
Page 757 and 758:
708 antidiuretic response to vasopr
Page 759 and 760:
710 antidiuretic activity without i
Page 761 and 762:
Page 763 and 764:
714 Mild facial flushing and headac
Page 765 and 766:
Table 25-9Vasopressin Receptor Anta
Page 767 and 768:
718 Franse LV, Pahor M, Di Bari M,
Page 769 and 770:
Page 771 and 772:
722Angiotensinogen43 a.a. propeptid
Page 773 and 774:
724AGTAng I43 amino acidpropeptideA
Page 775 and 776:
726 in the locus p11.4 of the X chr
Page 777 and 778:
728 state, AngII may increase, decr
Page 779 and 780:
730 Normally, GFR is slightly reduc
Page 781 and 782:
Page 783 and 784:
734 metabolite, moexiprilat. Moexip
Page 785 and 786:
736 effective. Once ACE inhibitors
Page 787 and 788:
738 • ACE inhibitors may increase
Page 789 and 790:
(75-300 mg) reductions in blood pre
Page 791 and 792:
742 (LIFE): A randomized trial agai
Page 793 and 794:
744 Wallukat G, Homuth V, Fischer T
Page 795 and 796:
746Agents decreasing O 2 demandβ A
Page 797 and 798:
Table 27-1Organic Nitrates Availabl
Page 799 and 800:
750 consumption. An additional bene
Page 801 and 802:
752 angina when a nitrate-free inte
Page 803 and 804:
754 Transmucosal or Buccal Nitrogly
Page 805 and 806:
Table 27-2Ca 2+ Channel Blockers: C
Page 807 and 808:
758 increased modestly. After oral
Page 809 and 810:
760 Exertional Angina. Ca 2+ channe
Page 811 and 812:
Table 27-3Recommended Drug Therapy
Page 813 and 814:
764 a Ca 2+ channel blocker may pro
Page 815 and 816:
766 Hypertension is defined convent
Page 817 and 818:
Table 27-6Hemodynamic Effects of Lo
Page 819 and 820:
770 refractory to drugs that block
Page 821 and 822:
772 promotes endothelial cell depen
Page 823 and 824:
774 Methyldopa (α-methyl-3,4-dihyd
Page 825 and 826:
776 result of the lack of sympathet
Page 827 and 828:
778 normal renal function. However,
Page 829 and 830:
780 expression of hypoxia-inducible
Page 831 and 832:
782 ameliorated by a β receptor an
Page 833 and 834:
784 Stop Hypertension (DASH) diet m
Page 835 and 836:
786 Chaitman BR, Pepine CJ, Parker
Page 837 and 838:
788 Pedersen ME, Cockcroft JR. What
Page 839 and 840:
790 Congestive heart failure is the
Page 841 and 842:
792NormalCongestivesymptomsototoxic
Page 843 and 844:
794sympatheticstimulationBradykinin
Page 845 and 846:
Page 847 and 848:
798 counterproductive in symptomati
Page 849 and 850:
800 CHF and may represent one mecha
Page 851 and 852:
802 Mechanism of the Positive Inotr
Page 853 and 854:
804 recognition of digoxin toxicity
Page 855 and 856:
806Pressure (mm Hg)ESPVREDPVR(diast
Page 857 and 858:
808 acid level reduction (over 24 w
Page 859 and 860:
810 and management of end- stage CH
Page 861 and 862:
SECTION IIIMODULATION OF CARDIOVASC
Page 863 and 864:
Page 865 and 866:
816Na +0 mV -90 mV4 mM 150 mM0 mV -
Page 867 and 868:
818SA nodeAtriumAV nodePurkinje fib
Page 869 and 870:
820 MECHANISMS OF CARDIACARRHYTHMIA
Page 871 and 872:
822ADAD1accessorypathway2BEADSECTIO
Page 873 and 874:
Table 29-2A Mechanistic Approach to
Page 875 and 876:
826ABDecreasedphase 4slopeIncreased
Page 877 and 878:
828 better characterized in a range
Page 879 and 880:
830 nodal function permits a greate
Page 881 and 882:
832 many arrhythmias than other β
Page 883 and 884:
834 ANTI-ARRHYTHMIC DRUGSSECTION II
Page 886:
Table 29-5Pharmacokinetic Character
Page 889 and 890:
838 Pharmacologic Effects. Digitali
Page 891 and 892:
840 atrial fibrillation. However, d
Page 893 and 894:
842 fall. To avoid this distributio
Page 895 and 896:
Page 897 and 898:
846 initially tolerating antiarrhyt
Page 899 and 900:
848 Stewart RB, Bardy GH, Greene HL
Page 901 and 902:
850Endothelial cellsPlatelets+COX-1
Page 903 and 904:
852 formation of a superimposed thr
Page 905 and 906:
About 10-15 glycosaminoglycan chain
Page 907 and 908:
856AUnfractionedheparinFactorXaPent
Page 909 and 910:
858 For therapeutic purposes, hepar
Page 911 and 912:
860 Bivalirudin contains the sequen
Page 913 and 914:
862 with the functional level of pr
Page 915 and 916:
864 inhibits platelet function. Eld
Page 917 and 918:
866 Dabigatran etexilate is approve
Page 919 and 920:
868 indications as aminocaproic aci
Page 921 and 922:
870 for clopidogrel are to reduce t
Page 923 and 924:
872 approved, ticagrelor is the fir
Page 925 and 926:
874 has received anticoagulant or a
Page 927 and 928:
876 Varmus H, eds. The Molecular Ba
Page 929 and 930:
878 to as “small, dense LDL”) (
Page 932:
Page 935 and 936:
882 increasing triglyceride- and ch
Page 937 and 938:
884 Tangier disease, a genetic diso
Page 939 and 940:
Table 31-3Treatment Based on LDL-C
Page 941 and 942:
Table 31-6Assessing 10-Year Risk of
Page 943 and 944:
Page 945 and 946:
Treatment of HypertriglyceridemiaTh
Page 947 and 948:
894 Figure 31-2 along with the reac
Page 949 and 950:
896 Due to extensive first-pass hep
Page 951 and 952:
898 unless the patient also is taki
Page 953 and 954:
900 Niacin is a water-soluble B-com
Page 955 and 956:
902 Mechanism of Action. Despite ex
Page 957 and 958:
904 diminished remnant cholesterol
Page 959 and 960:
906 D’Agostino RB Sr, Vasan RS, P
Page 961 and 962:
908 Prueksaritanont T, Tang C, Qiu
Page 963 and 964:
Page 965 and 966:
912 antagonists has yet emerged as
Page 967 and 968:
914 Regulation of Mediator Release.
Page 969 and 970:
916 of H receptor subtypes on neigh
Page 971 and 972:
918 by H 2blockade. In asthmatic su
Page 973 and 974:
920 et al., 2002). Thus, the develo
Page 975 and 976:
Table 32-2Preparations and Dosage o
Page 977 and 978:
924 Ethylenediamines (Prototype: Py
Page 979 and 980:
926 Caution should be used in treat
Page 981 and 982:
Table 32-3Structure of Kinin Agonis
Page 983 and 984:
930Aminopeptidase PKininase I(Carbo
Page 985 and 986:
932 thrombin generation following c
Page 987 and 988:
934 Leeb-Lundberg LM, Marceau F, Mu
Page 989 and 990:
Page 991 and 992:
938SECTION IVINFLAMMATION, IMMUNOMO
Page 993 and 994:
Page 995 and 996:
942 cytoprotective PGs in the GI tr
Page 997 and 998:
of the TP (α and β), FP (A and B)
Page 999 and 1000:
946 receptors have limited distribu
Page 1001 and 1002:
948 dysfunctional ROMK2, also is kn
Page 1003 and 1004:
950 inflammation by increasing endo
Page 1005 and 1006:
952 ligands such as oxidized lipids
Page 1007 and 1008:
954 Physiological and Pathological
Page 1009 and 1010:
956 FitzGerald GA. Mechanisms of pl
Page 1011 and 1012:
Page 1013 and 1014:
960 face of environmental pathogens
Page 1015 and 1016:
962 endogenous pyrogens. The initia
Page 1017 and 1018:
964 COX-2, and thus COX-2-mediated
Page 1019:
Page 1023:
Page 1027:
970SECTION IVTable 34-1Classificati
Page 1030 and 1031:
972 However, low-dose aspirin is no
Page 1032 and 1033:
974 warfarin (12-fold), glucocortic
Page 1034 and 1035:
976 implicated in Reye’s syndrome
Page 1036 and 1037:
978 capillary permeability during i
Page 1038 and 1039:
980 after initiation of therapy is
Page 1040 and 1041:
982 result of three processes. Firs
Page 1042 and 1043:
984 Management of Acetaminophen Ove
Page 1044 and 1045:
986 Adverse Effects. Etodolac appea
Page 1046 and 1047:
Page 1048 and 1049:
990 After absorption, piroxicam is
Page 1050 and 1051:
992 attributable to COX-2-selective
Page 1052 and 1053:
Table 34-3Disease-Modifying Anti-Rh
Page 1054 and 1055:
996 year, and 0.6 mg two or three t
Page 1056 and 1057:
998 complex with both the reduced a
Page 1058 and 1059:
1000 refractory to other drugs used
Page 1060 and 1061:
1002 Davies NM, Anderson KE. Clinic
Page 1062 and 1063:
1004 Solomon SD, McMurray JJ, Pfeff
Page 1064 and 1065:
1006 the induction and maintenance
Page 1066 and 1067:
1008 other immunosuppressive agents
Page 1068 and 1069:
1010TCRSECTION IVINFLAMMATION, IMMU
Page 1070 and 1071:
1012 gout, increased P-glycoprotein
Page 1072 and 1073:
1014 common), and/or anemia (uncomm
Page 1074 and 1075:
1016 have overcome the problems of
Page 1076 and 1077:
1018 cyclosporine and prednisone. I
Page 1078 and 1079:
1020 trials. Because they remain ex
Page 1080 and 1081:
1022 with erythema nodosum leprosum
Page 1082 and 1083:
Table 35-2Selected Immune Globulin
Page 1084 and 1085:
agent that ameliorates auto-immune
Page 1086 and 1087:
1028 Eisen HJ, Tuzcu EM, Dorent R,
Page 1088 and 1089:
Page 1090 and 1091:
1032AllergenDendritic cellMast cell
Page 1092 and 1093:
1034 ROUTES OF DRUG DELIVERYTO THE
Page 1094 and 1095:
1036NOREPINEPHRINEHO CH CH 2 NH 2HO
Page 1096 and 1097:
1038 the treatment of asthma due to
Page 1098 and 1099:
1040 a marked increase in the risk
Page 1100 and 1101:
1042SECTION IVINFLAMMATION, IMMUNOM
Page 1102 and 1103:
1044 is the first drug to demonstra
Page 1104 and 1105:
1046 including glycopyrrolate and a
Page 1106 and 1107:
1048Inflammatory stimulie.g. IL-1β
Page 1108 and 1109:
1050 Routes of Administration and D
Page 1110 and 1111:
1052 lung function than if treatmen
Page 1112 and 1113:
1054 were not on concomitant cortic
Page 1114 and 1115:
1056 IL-4 and IL-13, which determin
Page 1116 and 1117:
1058 (Dicpinigaitis, 2009a). It can
Page 1118 and 1119:
1060AEndothelial factors influencin
Page 1120 and 1121:
1062 Clark AR. MAP kinase phosphata
Page 1122 and 1123:
1064 Nathani N, Little MA, Kunst H,
Page 1124 and 1125:
Page 1126 and 1127:
1068 Individual growth factors then
Page 1128 and 1129:
Table 37-1Hematopoietic Growth Fact
Page 1130 and 1131:
1072 estimated as ~17% based on a m
Page 1132 and 1133:
1074 reduced without a change in lo
Page 1134 and 1135:
1076 and many other organs. In both
Page 1136 and 1137:
1078 (IRP1 and IRP2). Double knocko
Page 1138 and 1139:
1080SECTION IVINFLAMMATION. IMMUNOM
Page 1140 and 1141:
1082 limits the entry of iron into
Page 1142 and 1143:
1084 follows usual oral doses. Comm
Page 1144 and 1145:
SECTION IVINFLAMMATION. IMMUNOMODUL
Page 1146 and 1147:
1088 methyl group to cobalamin is e
Page 1148 and 1149:
1090 intracellular storage proteins
Page 1150 and 1151:
1092 neurological signs or symptoms
Page 1152 and 1153:
1094 DIETLiverdisease and for venou
Page 1154 and 1155:
1096 seventh days; the reticulocyte
Page 1156 and 1157:
1098 Hoffbrand AV, Herbert V. Nutri
Page 1158 and 1159:
Page 1160 and 1161:
Page 1162 and 1163:
disorders. Chapters 38 through 44 d
Page 1164 and 1165:
Table 38-2Properties of the Protein
Page 1166 and 1167:
1108SECTION VHORMONES AND HORMONE A
Page 1168 and 1169:
1110AGHBGHGHPegvisomantGHRGHRGHRGHR
Page 1170 and 1171:
1112 Clinical Manifestations of Gro
Page 1172 and 1173:
1114 provides a highly effective al
Page 1174 and 1175:
1116 ZORBTIVE); somatrem refers to
Page 1176 and 1177:
Page 1179 and 1180:
1120 Gonadotropin production also i
Page 1181 and 1182:
1122 to therapeutic advantage in a
Page 1183 and 1184:
1124 detect the presence of an ecto
Page 1185 and 1186:
1126 CLINICAL SUMMARYSECTION VHORMO
Page 1187 and 1188:
Page 1189 and 1190:
1130 important role in energy metab
Page 1191 and 1192:
1132BasolateralmembraneApicalmembra
Page 1193 and 1194:
Table 39-1Properties of Iodothyroni
Page 1195 and 1196:
Page 1197 and 1198:
1138 whereas dairy products and fis
Page 1199 and 1200:
1140 it is the effects of unligande
Page 1201 and 1202:
1142 types of thyroid dysfunction,
Page 1203 and 1204:
1144 Subclinical Hypothyroidism. Su
Page 1205 and 1206:
1146 of patients and hence have lit
Page 1207 and 1208:
1148 have weak anti-thyroid action
Page 1209 and 1210:
1150 then the lower maintenance dos
Page 1211 and 1212:
1152 cigarette smoking has been rep
Page 1213 and 1214:
1154 Untoward Reactions. Occasional
Page 1215 and 1216:
1156 when prolonged treatment with
Page 1217 and 1218:
1158 Bartalena L, Marcocci C, Tanda
Page 1219 and 1220:
1160 combination of methimazole and
Page 1221 and 1222:
Page 1223 and 1224:
Page 1225 and 1226:
1166 Estrogens appear to play impor
Page 1227 and 1228:
1168AFOLLICULAR PHASELUTEAL PHASEBF
Page 1229 and 1230:
1170 Estrogens have positive effect
Page 1231 and 1232:
1172AERERTATAAAgonistEEGGTCAnnnTGAC
Page 1233 and 1234:
1174 FEMRING) may be used for slow
Page 1235 and 1236:
1176 population continues to age. O
Page 1237 and 1238:
1178 Tamoxifen is a triphenylethyle
Page 1239 and 1240:
1180 increase the risk of ovarian c
Page 1241 and 1242:
1182 with the fetal adrenal glands,
Page 1243 and 1244:
1184 Therapeutic UsesThe two most f
Page 1245 and 1246:
1186 capacity to supply food, energ
Page 1247 and 1248:
1188 events in women without other
Page 1249 and 1250:
1190 is discontinued. These agents
Page 1251 and 1252:
1192 Grumbach MM, Auchus RJ. Estrog
Page 1253 and 1254:
1194 Van Den Bemd GJ, Kuiper GG, Po
Page 1255 and 1256:
119621H 3 C 20H 3 C1711CH 3side cha
Page 1257 and 1258:
1198 (Gln) 20 (Pro) 8 (Gly) 23 arom
Page 1259 and 1260:
1200 After Completion of Puberty. W
Page 1261 and 1262:
1202 ATestosterone Enanthateenjoyed
Page 1263 and 1264:
1204 Side Effects. All androgens su
Page 1265 and 1266:
1206 to dihydrotestosterone, which
Page 1267 and 1268:
Page 1269 and 1270:
1210 the role of the hypothalamus i
Page 1271 and 1272:
1212CYP11A1HOH 3 CH 3 CH 3 C11C8B19
Page 1273 and 1274:
1214 G q-PLC-IP 3-Ca 2+ pathway to
Page 1275 and 1276:
of corticosteroids—one of the maj
Page 1277 and 1278:
1218 to the nucleus. There, it inte
Page 1279 and 1280:
1220 effect of other agents, such a
Page 1281 and 1282:
suppression of inflammation is of e
Page 1283 and 1284:
1224 (e.g., corticosterone) have ap
Page 1285 and 1286:
Table 42-4Available Preparations of
Page 1287 and 1288:
1228 and error and must be the lowe
Page 1289 and 1290:
1230 mineralocorticoid used is flud
Page 1291 and 1292:
1232 Ocular Diseases. Ocular pharma
Page 1293 and 1294:
1234 and 11-deoxycortisol are measu
Page 1295 and 1296:
Page 1297 and 1298:
1238A Fasting state B Prandial stat
Page 1299 and 1300:
1240 interplay of various nutrients
Page 1301 and 1302:
1242SECTION VInsulinreceptorαβY-S
Page 1303 and 1304:
Table 43-2Different Forms of Diabet
Page 1305 and 1306:
1246 fasting. Beyond the defect in
Page 1307 and 1308:
1248 Therapy of DiabetesSECTION VHO
Page 1309 and 1310:
Commercial preparations of insulin
Page 1311 and 1312:
1252 which stabilizes the insulin h
Page 1313 and 1314:
1254 new cases of pediatric diabete
Page 1315 and 1316:
Table 43-7Structural Formulas of th
Page 1317 and 1318:
Nateglinide is metabolized primaril
Page 1319 and 1320:
1260 and their specific role in the
Page 1321 and 1322:
1262ProglucagonGRPP Glucagon IP-1 G
Page 1323 and 1324:
1264 DPP-4 InhibitorsMechanism of A
Page 1325 and 1326:
Page 1327:
Page 1331 and 1332:
1270 system that prevents acute hyp
Page 1333 and 1334:
1272 Concannon P, Rich SS, Nepom GT
Page 1335 and 1336:
Page 1337 and 1338:
12761092.5Intestine:800 mg intakeBo
Page 1339 and 1340:
1278 removed by extrarenal mechanis
Page 1341 and 1342:
1280 response to positive or negati
Page 1343 and 1344:
Page 1345 and 1346:
1284Calcitonin/katacalcin/CGRPgene5
Page 1347 and 1348:
1286Bone lining cellsBoneOsteoclast
Page 1349 and 1350:
1288 25-hydroxy- and 1,25-dihydroxy
Page 1351 and 1352:
1290 deposition in bone, once a cau
Page 1353 and 1354:
1292OHSECTION VHOOH1OHD 3alphacalci
Page 1355 and 1356:
1294 uses of vitamin D are discover
Page 1357 and 1358:
1296 has been supplanted largely by
Page 1359 and 1360:
1298 cinacalcet improves outcomes s
Page 1361 and 1362:
1300 cancer, and coronary events (c
Page 1363 and 1364:
1302 enamel. Osteosclerosis is char
Page 1365 and 1366:
1304 Greenspan SL, Bone HG, Ettinge
Page 1367 and 1368:
1306 Van Cromphaut SJ, Dewerchin M,
Page 1369 and 1370:
Page 1371 and 1372:
1310GastrinMuscarinicantagonistsSEC
Page 1373 and 1374:
1312 • enteric-coated granules su
Page 1375 and 1376:
1314 within 1-3 hours. Absorption m
Page 1377 and 1378:
Table 45-2Composition and Acid Neut
Page 1379 and 1380:
1318Severity of GERDStage ISporadic
Page 1381 and 1382:
1320 that H. pylori plays a major e
Page 1383 and 1384:
1322 Norgard NB, Mathews KD, Wall G
Page 1385 and 1386:
1324ORAL4ANALLM26135+ + - - -7MPCMS
Page 1387 and 1388:
1326 Metoclopramide is available in
Page 1389 and 1390:
1328 undigested food into the small
Page 1391 and 1392:
The terms laxatives, cathartics, pu
Page 1393 and 1394:
1332SECTION VIDRUGS AFFECTING GASTR
Page 1395 and 1396:
1334 have been used as laxatives. A
Page 1397 and 1398:
1336 sodium bicarbonate and potassi
Page 1399 and 1400:
1338 Loperamide N-oxide, an investi
Page 1401 and 1402:
1340 involvement in sensitization o
Page 1403 and 1404:
HIGHERCENTERSMemory, fear,dread, an
Page 1405 and 1406:
1344 AntihistaminesTable 46-7SECTIO
Page 1407 and 1408:
1346 component of nausea and vomiti
Page 1409 and 1410:
1348 options. For patients with gas
Page 1411 and 1412:
Page 1413:
1352SECTION VIDRUGS AFFECTING GASTR
Page 1416 and 1417:
1354 mediated inflammatory processe
Page 1418 and 1419:
1356 rapid acetylators have lower s
Page 1420 and 1421:
1358 liver function tests also may
Page 1422 and 1423:
1360 for the treatment of Crohn’s
Page 1424 and 1425:
1362 Prantera C, Cottone M, Pallone
Page 1426 and 1427:
Page 1428 and 1429:
1366SECTION VIICHEMOTHERAPY OF MICR
Page 1430 and 1431:
1368Absorption compartment (p)SECTI
Page 1432 and 1433:
Page 1434 and 1435:
1372 Third, optimal microbial kill
Page 1436 and 1437:
1374 colonization or infection by a
Page 1438 and 1439:
1376 penicillin that resistance dev
Page 1440 and 1441:
1378 or by subsequent transfers to
Page 1442 and 1443:
1380 Lewis K. Riddle of biofilm res
Page 1444 and 1445:
Page 1446 and 1447:
1384 hepatocyte infection as a dorm
Page 1448 and 1449:
Table 49-1Malarial Parasite Develop
Page 1450 and 1451:
Table 49-2Regimens for the Preventi
Page 1453:
Page 1457:
Page 1461:
Page 1464 and 1465:
1396 site. Both artesunate and arte
Page 1466 and 1467:
1398 recent study reported an incre
Page 1468 and 1469:
1400 The 2,4-diaminopyrimidines mor
Page 1470 and 1471:
1402 chloroquine and pyrimethamine-
Page 1472 and 1473:
1404 By studying the progeny of a g
Page 1474 and 1475:
1406 Chemistry. Cinchona contains a
Page 1476 and 1477:
1408 MefloquineSECTION VIICHEMOTHER
Page 1478 and 1479:
1410 Therapeutic or higher doses of
Page 1480 and 1481:
In general, dosing should be starte
Page 1482 and 1483:
1414 For clinical classification of
Page 1484 and 1485:
1416 Bray PG, Ward SA, O’Neill PM
Page 1486 and 1487:
1418 Valderramos SG, Fidock DA. Tra
Page 1488 and 1489:
1420 The organisms can be different
Page 1490 and 1491:
1422 African (Gambian), caused by T
Page 1492 and 1493:
1424 Isospora belli, a coccidian pa
Page 1494 and 1495:
1426 nifurtimox used in combination
Page 1496 and 1497:
1428 encephalopathy (the treatment-
Page 1498 and 1499:
1430 elapse between courses. In suc
Page 1500 and 1501:
1432 T. brucei and can be curative
Page 1502 and 1503:
1434 whereas children have been tre
Page 1504 and 1505:
1436 2006), where lipid-based ampho
Page 1506 and 1507:
1438 stomatitis, chills, abdominal
Page 1508 and 1509:
1440 surveillance study in HIV-infe
Page 1510 and 1511:
Page 1512 and 1513:
Page 1514 and 1515:
1446 hyperinfection. Ivermectin is
Page 1516 and 1517:
1448 Diphyllobothrium latum. Diphyl
Page 1518 and 1519:
Page 1520 and 1521:
1452 with combination therapy for 4
Page 1522 and 1523:
1454 (Addiss and Dreyer, 2000). Exp
Page 1524 and 1525:
1456 ivermectin (Molyneux et al., 2
Page 1526 and 1527:
1458 bioavailability of praziquante
Page 1528 and 1529:
1460 Dull HB, Meredith SE. The Mect
Page 1530 and 1531:
Page 1532 and 1533:
Page 1534 and 1535:
1466 readily than the free fraction
Page 1536 and 1537:
1468 Aplastic Anemia. Complete supp
Page 1538 and 1539:
1470 anti-Pneumocystis therapy in p
Page 1540 and 1541:
1472 DNA via an ATP-dependent react
Page 1542 and 1543:
1474 were also receiving theophylli
Page 1544 and 1545:
1476 Centers for Disease Control an
Page 1546 and 1547:
1478 was that of a policeman who wa
Page 1548 and 1549:
1480AGram positiveGram negativeSECT
Page 1550 and 1551:
1482 Classification of the Penicill
Page 1552 and 1553:
1484 1.5 million units every 8-12 h
Page 1554 and 1555:
1486 under controlled conditions, i
Page 1556 and 1557:
Table 53-1Chemical Structures and M
Page 1558 and 1559:
1490 increasingly common. Enterococ
Page 1560 and 1561:
1492 Serum sickness varies from mil
Page 1562 and 1563:
Table 53-2Names, Structural Formula
Page 1564 and 1565:
Table 53-3Cephalosporin Generations
Page 1566 and 1567:
1498 microorganisms than is the par
Page 1568 and 1569:
1500 Imipenem. Imipenem is marketed
Page 1570 and 1571:
1502 Brown EJ. The molecular basis
Page 1572 and 1573:
Page 1574 and 1575:
1506ACAC IAC IIAC IIIACAC IAC IIAC
Page 1576 and 1577:
Page 1578 and 1579:
1510 wounds, burns, or cutaneous ul
Page 1580 and 1581:
1512 (Knoderer et al., 2003; Rastog
Page 1582 and 1583:
1514 of the collecting-duct epithel
Page 1584 and 1585:
1516 vancomycin has been recommende
Page 1586 and 1587:
1518 Prophylactic Uses. Kanamycin c
Page 1588 and 1589:
1520 Luzzatto L, Apirion D, Schless
Page 1590 and 1591:
Table 55-1Structural Formulas of th
Page 1592 and 1593:
1524 Oral doses of doxycycline and
Page 1594 and 1595:
1526 Photosensitivity. Demeclocycli
Page 1596 and 1597:
1528 less toxic and because strains
Page 1598 and 1599:
1530 In general, organisms are cons
Page 1600 and 1601:
1532 failure. No dose has been esta
Page 1602 and 1603:
1534 gastric emptying in patients w
Page 1604 and 1605:
1536 streptogramin A, in a 30:70 ra
Page 1606 and 1607:
1538 Indiscriminant use and overuse
Page 1608 and 1609:
1540 Antimicrobial Activity. Vancom
Page 1610 and 1611:
1542 because these modalities clear
Page 1612 and 1613:
1544 dermal ulcers, the local appli
Page 1614 and 1615:
1546 review of the published eviden
Page 1616 and 1617:
Page 1618 and 1619:
Page 1620 and 1621:
Page 1622 and 1623:
1554 Rifamycin Overdose. Rifampin o
Page 1624 and 1625:
1556 Other products of KatG activat
Page 1626 and 1627:
appear during the use of this drug,
Page 1628 and 1629:
1560 ClofazimineClofazimine (LAMPRE
Page 1630 and 1631:
1562 acid synthase II (Larsen et al
Page 1632 and 1633:
1564 Anti-parasitic. Dapsone is als
Page 1634 and 1635:
1566 Therapy of MAC Pulmonary Infec
Page 1636 and 1637:
Page 1638 and 1639:
1570 Orenstein EW, Basu S, Shah NS,
Page 1640 and 1641:
Page 1642 and 1643:
Table 57-2Pharmocokinetic Parameter
Page 1644 and 1645:
1576 with cryptococcosis, but the c
Page 1646 and 1647:
Table 57-6Some Additional Contraind
Page 1648 and 1649:
1580 excretion accounts for >90% of
Page 1650 and 1651:
1582 13 days. Posaconazole is appro
Page 1652 and 1653:
1584 Metabolism and Excretion. Cata
Page 1654 and 1655:
1586 and severe angioedema develop
Page 1656 and 1657:
1588 Oxiconazole, Sulconazole, and
Page 1658 and 1659:
1590 De Pauw BE, Donnelly JP. Proph
Page 1660 and 1661:
Page 1662 and 1663:
Table 58-1Stages of Virus Replicati
Page 1664 and 1665:
Table 58-2Nomenclature of Antiviral
Page 1666 and 1667:
1598HerpessimplexCytoplasmSECTION V
Page 1668 and 1669:
1600 and adults. In children weighi
Page 1670 and 1671:
1602 Absorption, Distribution, and
Page 1672 and 1673:
1604 and Faulds, 1998). Inhibitory
Page 1674 and 1675:
Page 1676 and 1677:
1608 amantadine or rimantadine trea
Page 1678 and 1679:
1610 without known airway disease,
Page 1680 and 1681:
Page 1682 and 1683:
Page 1684 and 1685:
1616 anti-HBV nucleosides show enha
Page 1686 and 1687:
1618 ≥41% of patients, and reduct
Page 1688 and 1689:
1620 De Clercq E. Clinical potentia
Page 1690 and 1691:
1622 for cytomegalovirus retinitis
Page 1692 and 1693:
1624 clade per se does not seem to
Page 1694 and 1695:
1626 control but also complicates t
Page 1696 and 1697:
1628 Failure of an antiretroviral r
Page 1698:
Page 1701 and 1702:
1632 eliminated from the body prima
Page 1703 and 1704:
1634 accumulate in the cell, and th
Page 1705 and 1706:
1636 Carbovir, a related guanine an
Page 1707 and 1708:
1638 atazanavir increases the tenof
Page 1709 and 1710:
1640 generally can be avoided by se
Page 1711 and 1712:
Table 59-3Pharmacokinetic Propertie
Page 1713 and 1714:
1644 effective in patients who have
Page 1715 and 1716:
1646SECTION VIINOHNH 2 NONHOOHONHNH
Page 1718 and 1719:
Page 1720 and 1721:
1650 the low doses used for this pu
Page 1722 and 1723:
1652 diarrhea, nausea, and vomiting
Page 1724 and 1725:
1654 In treatment-naive patients re
Page 1726 and 1727:
1656 tipranavir/ritonavir or a comp
Page 1728 and 1729:
1658 with an intravenous dose (Dand
Page 1730 and 1731:
1660 In each of these settings, the
Page 1732 and 1733:
1662 Jayasekara D, Aweeka FT, Rodri
Page 1734 and 1735:
Page 1736 and 1737:
Page 1738 and 1739:
Table 60-1Alkylating AgentsNONPROPR
Page 1740 and 1741:
Table 60-4Hormones and AntagonistsN
Page 1742 and 1743:
1672SECTION VIIICHEMOTHERAPY OF NEO
Page 1744 and 1745:
1674 employed in traditional cytoto
Page 1746 and 1747:
Page 1748 and 1749:
Page 1750 and 1751:
Page 1752 and 1753:
is reversible at usual doses, but o
Page 1754 and 1755:
1684 However, adequate hydration an
Page 1756 and 1757:
1686 fall for >1 month after discon
Page 1758 and 1759:
1688 platinum complexes do not form
Page 1760 and 1761:
1690 intravenously and decline ther
Page 1762 and 1763:
1692Pteridine ringp-aminobenzoic ac
Page 1764 and 1765:
1694 four doses, alternating with l
Page 1766 and 1767:
1696Fluoropyrimidine AnalogsH 3 COH
Page 1768 and 1769:
1698 Intrahepatic arterial infusion
Page 1770 and 1771:
1700 the liposomal formulation is i
Page 1772 and 1773:
1702 de novo purine synthesis and a
Page 1774 and 1775:
1704 Cladribine is considered the d
Page 1776 and 1777:
1706 throughout the cytoplasm (expl
Page 1778 and 1779:
1708 prior to therapy is required t
Page 1780 and 1781:
1710 1.6 months with ixabepilone pl
Page 1782 and 1783:
1712 The recommended dosing regimen
Page 1784 and 1785:
1714 As discussed in “Drug Resist
Page 1786 and 1787:
1716 compromised renal function, do
Page 1788 and 1789:
1718 basilar infiltrates on X-ray a
Page 1790 and 1791:
1720 double-strand DNA breaks throu
Page 1792 and 1793:
1722 is a potent radiosensitizer as
Page 1794 and 1795:
1724 core, allowing access for tran
Page 1796 and 1797:
1726 resistance against anticancer
Page 1798 and 1799:
1728 reductase activity contributes
Page 1800 and 1801:
1730 Westerhof GR, Rijnboutt S, Sch
Page 1802 and 1803:
Page 1804 and 1805:
1734 imatinib, as a competitive CYP
Page 1806 and 1807:
1736 Mechanism of Action. Erlotinib
Page 1808 and 1809:
1738 ErbB1 and ErbB2 and bind to an
Page 1810 and 1811:
1740 In colon cancer patients, colo
Page 1812 and 1813:
1742 and rapidly interconverting no
Page 1814 and 1815:
1744OHOcellmembraneIGF1ROther TK re
Page 1816 and 1817:
Table 62-1Monoclonal Antibodies App
Page 1818 and 1819:
1748 from the site targeted by ritu
Page 1820 and 1821:
1750 good performance status and no
Page 1822 and 1823:
1752 patients with CD33-positive ac
Page 1824 and 1825:
Page 1826 and 1827:
Page 1828 and 1829:
1758ONCH 3CH 3CH 3 O CH 3NSECTION V
Page 1830 and 1831:
1760 Steady-state concentrations ar
Page 1832 and 1833:
1762 administered once daily for 28
Page 1834 and 1835:
1764SECTION VIIICHEMOTHERAPY AND TA
Page 1837 and 1838:
1766 Available Anti-Androgens. Anti
Page 1839 and 1840:
1768 cancer in postmenopausal women
Page 1841 and 1842:
Page 1843 and 1844:
Page 1845 and 1846:
1774Superior oblique muscleLevator
Page 1847 and 1848:
1776SECTION IXSPECIAL SYSTEMS PHARM
Page 1849 and 1850:
covered by an episcleral vascular c
Page 1851 and 1852:
1780 Transcorneal and transconjunct
Page 1853 and 1854:
1782 The more commonly reported inf
Page 1855 and 1856:
Table 64-6Antifungal Agents for Oph
Page 1857 and 1858:
Table 64-7Autonomic Drugs for Ophth
Page 1859 and 1860:
1788 Such combinations reduce the n
Page 1861 and 1862:
1790 subconjunctivally during the p
Page 1863 and 1864:
Page 1865 and 1866:
1794 myopia and presumed ocular his
Page 1867 and 1868:
ACH 3CH 3C 7 10 151 H 2 C 6 C CH CH
Page 1869 and 1870:
1798 and reduce the synthesis of ot
Page 1871 and 1872:
1800 Fluorouracil Filtering Surgery
Page 1873 and 1874:
Page 1875 and 1876:
1804Shunt diffusionPermeationPenetr
Page 1877 and 1878:
Page 1879 and 1880:
Table 65-3Potency of Selected Topic
Page 1881 and 1882:
Table 65-4Topical RetinoidsRECEPTOR
Page 1883 and 1884:
Page 1885 and 1886:
Table 65-6Photochemotherapy Methods
Page 1887 and 1888:
Table 65-7Half-Life of Antihistamin
Page 1889 and 1890:
Page 1891 and 1892:
1820 CYTOTOXIC AND IMMUNOSUPPRESSIV
Page 1893 and 1894:
1822 Tacrolimus. Tacrolimus (FK506,
Page 1895 and 1896:
1824 An initial dosage of 50 mg/day
Page 1897 and 1898:
1826EpidermisNon-lesional skinAntig
Page 1899 and 1900:
evokes the same reaction on skin wi
Page 1901 and 1902:
Page 1903 and 1904:
1832 Repka-Ramirez MS, Baraniuk JN.
Page 1905 and 1906:
1834SECTION IXTable 66-1One-Year Fa
Page 1907 and 1908:
Table 66-2Brand Names and Formulati
Page 1909 and 1910:
1838 sex steroid hormones; are used
Page 1911 and 1912:
1840 Finally, some clinicians use a
Page 1913 and 1914:
Page 1915 and 1916:
1844A.Gonadotropin (IU)757575757575
Page 1917 and 1918:
1846 In pregnant women, the placent
Page 1919 and 1920:
1848 Although incompletely understo
Page 1921 and 1922:
1850 cesarean section in labor indu
Page 1923 and 1924:
1852 Olive DL. Gonadotropin-releasi
Page 1925 and 1926:
Page 1927 and 1928:
Table 67-1Examples of Important Car
Page 1929 and 1930:
Table 67-2Chemopreventive Agents Be
Page 1931 and 1932:
1860 Carcinogenicity. The primary c
Page 1933 and 1934:
1862 type (ATSDR, 2007b; Levin et a
Page 1935 and 1936:
1864BLOOD LEAD (μg/dL)Children Adu
Page 1937 and 1938:
1866 divalent (mercuric, Hg 2+ ) an
Page 1939 and 1940:
1868AFairbanks,AlaskaSECTION IXAleu
Page 1941 and 1942:
1870 Skin. The skin is very sensiti
Page 1943 and 1944:
1872 sulfate and phosphate and can
Page 1945 and 1946:
1874 appearance of chills and fever
Page 1947 and 1948:
Page 1949 and 1950:
1878 development of hepatocellular
Page 1951 and 1952:
1880APPENDIX ISuperscriptionPRINCIP
Page 1953 and 1954:
1882APPENDIX IPRINCIPLES OF PRESCRI
Page 1955 and 1956:
1884 >750 pairs of potentially conf
Page 1957 and 1958:
1886 if available. The USP maintain
Page 1959 and 1960:
1888 negative impact, that the ther
Page 1961 and 1962:
Page 1963 and 1964:
1892 has been selected from the lit
Page 1965 and 1966:
1894 To be accurate, clearances mus
Page 1967 and 1968:
1896 sustained-release product. Ind
Page 1969 and 1970:
1898 Because t 1/2has been the para
Page 1972:
1900APPENDIX IIDESIGN AND OPTIMIZAT
Page 1976:
Page 1980:
Page 1984:
Page 1988:
Page 1992:
Page 1996:
Page 2000:
Page 2004:
Page 2008:
Page 2012:
Page 2016:
Page 2020:
Page 2024:
Page 2028:
Page 2032:
Page 2036:
Page 2040:
Page 2044:
Page 2048:
Page 2052:
Page 2056:
Page 2060:
Page 2064:
Page 2068:
Page 2072:
Page 2076:
Page 2080:
Page 2084:
Page 2088:
Page 2092:
Page 2096:
Page 2100:
Page 2104:
Page 2108:
Page 2112:
Page 2116:
Page 2120:
Page 2124:
Page 2128:
Page 2132:
Page 2136:
Page 2140:
Page 2144:
Page 2148:
Page 2152:
Page 2155 and 2156:
1992INDEXAcetohexamide, 1257tAcetyl
Page 2157 and 2158:
1994INDEXAlendronate, pharmacokinet
Page 2159 and 2160:
1996INDEXAnalgesia/analgesics (Cont
Page 2161 and 2162:
1998INDEXAnthracyclines, 1713-1715l
Page 2163 and 2164:
2000INDEXAntioxidants, for pulmonar
Page 2165 and 2166:
2002INDEXAtorvastatin (Cont.):dosag
Page 2167 and 2168:
2004INDEXBenztropine, as antidote,
Page 2169 and 2170:
2006INDEXBortezomib (Cont.):mechani
Page 2171 and 2172:
2008INDEXCAPOTEN (captopril), 732-7
Page 2173 and 2174:
2010INDEXCelecoxib (Cont.):COX isof
Page 2175 and 2176:
2012INDEXChurg-Strauss angiitis,cyc
Page 2177 and 2178:
2014INDEXCompound 48/80, histamine
Page 2179 and 2180:
2016INDEXCytochrome P450CYP3A4, 897
Page 2181 and 2182:
2018INDEXDiabetes mellitus (DM) (Co
Page 2183 and 2184:
2020INDEXDiuretics (Cont.):inhibito
Page 2185 and 2186:
2022INDEXDYRENIUM (triamterene), 69
Page 2187 and 2188:
2024INDEXEpidermisand cutaneous dru
Page 2189 and 2190:
2026INDEXEtretinate (Cont.):standar
Page 2191 and 2192:
2028INDEXFlumazenil, 468-469, 1059a
Page 2193 and 2194:
2030INDEXGELUSIL II, 1316tGemcitabi
Page 2195 and 2196:
2032INDEXGynecology, drug therapy i
Page 2197 and 2198:
2034INDEXHistamine H 1receptor anta
Page 2199 and 2200:
2036INDEXHypobetalipoproteinemia, 8
Page 2201 and 2202:
2038INDEXInsulin (Cont.):as antidot
Page 2203 and 2204:
2040INDEXKKallidin, 926-932, 927f[d
Page 2205 and 2206:
2042INDEXLice, 1818-1819Lichen plan
Page 2207 and 2208:
2044INDEXLymphoma(s), 1755drugs for
Page 2209 and 2210:
2046INDEXMetabolism of drugs (Cont.
Page 2211 and 2212:
2048INDEXMisuse, poisoning and, 80M
Page 2213 and 2214:
2050INDEXMyocardial oxygen supply,p
Page 2215 and 2216:
2052INDEXNeurotransmitters (Cont.):
Page 2217 and 2218:
2054INDEXNorepinephrine, 287-288adv
Page 2219 and 2220:
2056INDEXOral contraceptives (Cont.
Page 2221 and 2222:
2058INDEXParturitioneicosanoids and
Page 2223 and 2224:
2060INDEXPhenytoin (Cont.):hypoglyc
Page 2225 and 2226:
2062INDEXPolymyxins, 1538-1539Polyt
Page 2227 and 2228:
2064INDEXPropidium, 241PROPINE (epi
Page 2229 and 2230:
2066INDEXQT interval, prologation,
Page 2231 and 2232:
2068INDEXRenin inhibitors, direct (
Page 2233 and 2234:
2070INDEXSalivary secretion, muscar
Page 2235 and 2236:
2072INDEXSmooth muscleamphetamines
Page 2237 and 2238:
2074INDEXSucralfateadverse effects
Page 2239 and 2240:
2076INDEXTenecteplase, 866Teniposid
Page 2241 and 2242:
2078INDEXTOLINASE (tolazamide), 125
Page 2243 and 2244:
2080INDEXTrospium chloride, 231, 23
Page 2245 and 2246:
2082INDEXVecuroniumcharacteristics
Page 2247:
2084INDEXXXALATAN (latanoprost), 17
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DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010