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

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92Clearance organs(liver, kidney)Concentrationin plasmaConcentrationin target organSECTION IDecreasesin uptake orexcretionDecreasestotalclearanceIncreasesexposureGENERAL PRINCIPLESToxicological target organs(liver, kidney, brain, etc.)TimeConcentrationin target organTimeIncreaseduptakeDecreasedeffluxIncreasesexposureTimeTarget organs(e.g., liver)DrugsPlasma or target organconcentration ofendogenous compoundChange intransport ofendogenouscompounds (•)AccumulationEndogenouscompoundsFigure 5–3. Major mechanisms by which transporters mediate adverse drug responses. Three cases are given. The left panel of eachcase provides a cartoon representation of the mechanism; the right panel shows the resulting effect on drug levels. (Top panel) Increasein 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 reducedefflux of the drug. (Bottom panel) Increase in the plasma concentration of an endogenous compound (e.g., a bile acid) due to a drug’sinhibiting the influx of the endogenous compound in its eliminating or target organ. The diagram also may represent an increase inthe concentration of the endogenous compound in the target organ owing to drug-inhibited efflux of the endogenous compound.Timehypoglycemic agents for the treatment of type II diabetes mellitus,can produce lactic acidosis, a lethal side effect. Phenformin was withdrawnfrom the market for this reason. Biguanides are substrates ofthe organic cation transporter OCT1, which is highly expressed in theliver. After oral administration of metformin, the distribution of thedrug to the liver in oct1(–/–) mice is markedly reduced compared withthe distribution in wild-type mice. Moreover, plasma lactic acid concentrationsinduced by metformin are reduced in oct1(–/–) mice
compared with wild-type mice, although the plasma concentrationsof metformin are similar in the wild-type and knockout mice. Theseresults indicate that the OCT1-mediated hepatic uptake of biguanidesplays an important role in lactic acidosis (Wang et al., 2003).The organic anion transporter 1 (OAT1) and organic cationtransporters (OCT1 and OCT2) provide other examples of transporterrelatedtoxicity. OAT1 is expressed mainly in the kidney and is responsiblefor the renal tubular secretion of anionic compounds. Substrates ofOAT1, such as cephaloridine (a β-lactam antibiotic), and adefovir andcidofovir (antiviral drugs), reportedly cause nephrotoxicity. In vitroexperiments suggest that cephaloridine, adefovir, and cidofovir are substratesof OAT1 and that OAT1-expressing cells are more susceptible tothe toxicity of these drugs than control cells (Ho et al., 2000; Takedaet al., 1999). Exogenous expression of OCT1 and OCT2 enhances thesensitivities of tumor cells to the cytotoxic effect of oxaliplatin forOCT1, and cisplatin and oxaliplatin for OCT2 (Zhang et al., 2006b).Drugs may modulate transporters for endogenous ligands andthereby exert adverse effects (Figure 5–3, bottom panel). For example,bile acids are taken up mainly by Na + -taurocholate cotransportingpolypeptide (NTCP) (Hagenbuch et al., 1991) and excreted intothe bile by the bile salt export pump (BSEP, ABCB11) (Gerloffet al., 1998). Bilirubin is taken up by OATP1B1 and conjugated withglucuronic acid, and bilirubin glucuronide is excreted by the multidrugresistance-associatedprotein (MRP2, ABCC2). Inhibition of thesetransporters by drugs may cause cholestasis or hyperbilirubinemia.Troglitazone, a thiazolidinedione insulin-sensitizing drug used forthe treatment of type II diabetes mellitus, was withdrawn from themarket because it caused hepatotoxicity. The mechanism for thistroglitazone-induced hepatotoxicity remains unclear. One hypothesisis that troglitazone and its sulfate conjugate induced cholestasis.Troglitazone sulfate potently inhibits the efflux of taurocholate (K i=0.2 μM) mediated by the ABC transporter BSEP. These findings suggestthat troglitazone sulfate induces cholestasis by inhibition ofBSEP function. BSEP-mediated transport is also inhibited by otherdrugs, including cyclosporin A and the antibiotics rifamycin andrifampicin (Stieger et al., 2000).Thus, uptake and efflux transporters determinethe plasma and tissue concentrations of endogenouscompounds and xenobiotics, and thereby can influencethe systemic or site-specific toxicity of drugs.BASIC MECHANISMS OFMEMBRANE TRANSPORTTransporters Versus Channels. Both channels and transportersfacilitate the membrane permeation of inorganicions and organic compounds (Reuss, 2000). In general,channels have two primary states, open and closed, thatare totally stochastic phenomena. Only in the open state dochannels appear to act as pores for the selected ions, allowingtheir permeation across the plasma membrane. Afteropening, channels return to the closed state as a functionof time. In contrast, a transporter forms an intermediatecomplex with the substrate (solute), and subsequently aconformational change in the transporter induces translocationof the substrates to the other side of the membrane.Therefore, there is a marked difference in turnover ratesbetween channels and transporters. The turnover rate constantsof typical channels are 10 6 to 10 8 s –1 , whereas thoseof transporters are, at most, 10 1 to 10 3 s –1 . Because aparticular transporter forms intermediate complexes withspecific compounds (referred to as substrates), transportermediatedmembrane transport is characterized by saturabilityand inhibition by substrate analogs, as described in“Kinetics of Transport.”The basic mechanisms involved in solute transportacross biological membranes include passive diffusion,facilitated diffusion, and active transport. Active transportcan be further subdivided into primary and secondaryactive transport. These mechanisms are depicted inFigure 5–4 and described in the next sections.Passive Diffusion. Simple diffusion of a solute acrossthe plasma membrane consists of three processes: partitionfrom the aqueous to the lipid phase, diffusionacross the lipid bilayer, and repartition into the aqueousphase on the opposite side. Diffusion of any solute(including drugs) occurs down an electrochemicalpotential gradient of the solute.Such diffusion may be described by the equation:(Equation 5–1)where Δμ is the potential gradient, z is the charge valence of thesolute, E mis the membrane voltage, F is the Faraday constant, R isthe gas constant, T is the absolute temperature, C is the concentrationof the solute inside (i) and outside (o) of the plasma membrane. Thefirst term on the right side in Equation (5–1) represents the electricalpotential, and the second represents the chemical potential.For non-ionized compounds, the flux J owing to simple diffusionis given by Fick’s first law (permeability multiplied by theconcentration difference). For ionized compounds, the difference inelectrical potential across the plasma membrane needs to be takeninto consideration. Assuming that the electrical field is constant, theflux is given by the Goldman-Hodgkin-Katz equation:J =−⎛ C ⎞iΔ μ = zE F + RT Inm ⎜ ⎟⎝ C o ⎠P zE FRT⎡ C − C exp E F / RT⎢− exp( E F RT⎣⎢1/m )m i o m( )(Equation5–2)where P represents the permeability. The lipid and water solubilityand the molecular weight and shape of the solute are determinants of⎤⎥⎦⎥93CHAPTER 5MEMBRANE TRANSPORTERS AND DRUG RESPONSE
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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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Page 66 and 67: 42 signaling compounds are termed a
Page 68 and 69: 44 receptors, but because the endog
Page 70 and 71: 46 ligand-receptor complex, LR*. Th
Page 72 and 73: 48 agonist plus an effective concen
Page 74 and 75: 50SECTION IGENERAL PRINCIPLESPRESCR
Page 76 and 77: 52 constrained by compartmentation
Page 78 and 79: 54A. Activation by Ligand Binding o
Page 80 and 81: 56 Second MessengersSECTION IGENERA
Page 82 and 83: 58 markedly stimulates Ca 2+ flux,
Page 84 and 85: 60 voltage-gated (Jegla et al., 200
Page 86 and 87: 62SECTION IA(a) UnligandedreceptorI
Page 88 and 89: 64 from the complex allowing the p5
Page 90 and 91: 66 upon binding ligand. Other membe
Page 92 and 93: 68 FADD/TRAF2, and caspase 8, which
Page 94 and 95: 70 of cyclic GMP are also increased
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Page 98 and 99: 74100ADeathSECTION I% of Population
Page 100 and 101: 76SECTION IGENERAL PRINCIPLESisofor
Page 102 and 103: 78SECTION IGENERAL PRINCIPLESantago
Page 104 and 105: 80SECTION IGENERAL PRINCIPLESarrhyt
Page 106 and 107: 82SECTION IGENERAL PRINCIPLESThe in
Page 108 and 109: 84SECTION IGENERAL PRINCIPLESGastri
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Page 114 and 115: 90TherapeuticeffectMetabolismTExcre
Page 118 and 119: 94Passive transport (downhill trans
Page 120 and 121: 96SECTION IGENERAL PRINCIPLESNoncom
Page 122 and 123: Table 5-1Regulation of Transporter
Page 124 and 125: 100ExtracellularSECTION IGENERAL PR
Page 126 and 127: Table 5-2Families in the Human Solu
Page 128 and 129: Table 5-3The ATP Binding Cassette (
Page 130 and 131: Table 5-4ABC Transporters Involved
Page 132 and 133: 108SECTION IGENERAL PRINCIPLESIn th
Page 134 and 135: 110SECTION IGENERAL PRINCIPLESthe u
Page 136 and 137: 112SECTION IGENERAL PRINCIPLESOC +B
Page 138 and 139: 114SECTION IGENERAL PRINCIPLEStrans
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Page 148 and 149: 124SECTION IGENERAL PRINCIPLESconst
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Page 152 and 153: Table 6-2Major Reactions Involved i
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Page 156 and 157: 132SECTION IGENERAL PRINCIPLESreact
Page 158 and 159: 134SECTION IGENERAL PRINCIPLESSN-38
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Page 162 and 163: Table 6-4Indications and Unwanted S
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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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292HONOHHNH 3 COCOOHNHC(CH 3 ) 3HOH
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294 agonist that has twice the pote
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296 these receptors is high, althou
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298 CNS. Amphetamine is one of the
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300 treatment of attention-deficit/
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302 syndrome and idiopathic autonom
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304 transient or may respond to adj
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306Alkylating agentCH 3OCH 2 CHNCH
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308 Syncopal episodes also have occ
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310 ingestion of tyramine-containin
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312OOOOHHNOOHHNOBISOPROLOLBETAXOLOL
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314 Billman, 2000; Brodde and Miche
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316 The β receptors mediate activa
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318 treatment for patients with all
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320 for an individual patient shoul
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322SECTION IINEUROPHARMACOLOGYTable
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326 nadolol is its relatively long
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328 or membrane-stabilizing activit
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330 and possibly papaverine-like re
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332 Gupta S, Wright HM. Nebivolol:
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336SECTION IINEUROPHARMACOLOGYNH 2N
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Table 13-1Serotonin Receptor Subtyp
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340SECTION IINEUROPHARMACOLOGY5-HT
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Table 13-3Some Actions of 5-HT in t
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344 suppressant in the management o
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346HNHNSECTION IICH 2H 3 CNHSO 2 CH
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Table 13-6Natural and Semisynthetic
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350 mCPP, an active metabolite of t
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352 Oby AADC, the same enzyme that
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354ND1 receptor familyD2 receptor f
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356SECTION IINEUROPHARMACOLOGYMesoc
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358 receptor agonist and a weak D 1
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360 Delgado PL, Charney DS, Price L
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364 system and integrate somatic an
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366 from the bloodstream into the b
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368A Ion channels α 1 subunits for
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Table 14-1Subtypes of Ca 2+ Channel
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372SECTION IINEUROPHARMACOLOGYselec
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374Presynapticneuron11 107Neurotran
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376SECTION IINEUROPHARMACOLOGYParav
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(including penicillin and pentylene
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380 (NMDA) receptors and non- NMDA
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Table 14-4Subtypes of Muscarinic Re
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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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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
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642 termed fetal alcohol effects (F
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644 metabolites of the drug, especi
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646 Lemoine P, Harousseau H, Bortey
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650 an addiction. These variables c
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652 paucity of other options for pl
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654 Withdrawal signs and symptoms o
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656SECTION IINEUROPHARMACOLOGYA sig
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660 crosses the blood-brain barrier
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662 high school students has declin
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664 developed and tested in control
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666 demonstrated in humans, the cer
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668 Mason BJ. Acamprosate and naltr
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672Glomerulus1111210139(Outer Strip
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674CCCCCCCCCCCCCBB1convectivesolute
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676 7. As water and solutes accumul
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Table 25-1Excretory and Renal Hemod
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680 However, even with a high degre
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682 Effects on Urinary Excretion. O
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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