Table Of Content

Color Atlas of Pharmacology 3rd edition, revised and expanded Heinz Lüllmann, M.D. Lutz Hein, M.D. FormerProfessorandChairman Professor DepartmentofPharmacology DepartmentofPharmacology UniversityofKiel UniversityofFreiburg Germany Germany Klaus Mohr, M.D. Detlef Bieger, M.D. Professor ProfessorEmeritus DepartmentofPharmacology DivisionofMedicalSciences andToxicology FacultyofMedicine UniversityofBonn MemorialUniversityof Germany Newfoundland St.John’s,Newfoundland Canada With 170 color plates by Jürgen Wirth Thieme Stuttgart · New York IV LibraryofCongressCataloging-in-PublicationData Importantnote:Medicineisanever-changing scienceundergoingcontinualdevelopment.Re- TaschenatlasderPharmakologie.Englisch. search and clinical experience are continually Coloratlasofpharmacology/HeinzLuellmann... expanding our knowledge, in particular our [etal.];172colorplatesbyJuergenWirth.— knowledgeofpropertreatmentanddrugther- 3rded.,rev.andexpanded apy.Insofarasthisbookmentionsanydosageor p.;cm. application,readersmayrestassuredthatthe Rev.andexpandedtranslationof:Taschenatlas authors, editors, and publishers have made derPharmakologie.5thed.c2004. everyefforttoensurethatsuchreferencesare Includesbibliographicalreferencesandindex. inaccordancewiththestateofknowledgeat ISBN3-13-781703-X(GTV:alk.paper)— thetimeofproductionofthebook. ISBN1-58890-332-X(alk.paper) Nevertheless, this does not involve, imply, or 1.Pharmacology—Atlases.2.Pharmacology— expressanyguaranteeorresponsibilityonthe Handbooks,manuals,etc.[DNLM:1.Pharma- partofthepublishersinrespecttoanydosage cology—Atlases.2.Pharmacology—Handbooks. instructionsandformsofapplicationsstatedin 3.DrugTherapy—Atlases.4.DrugTherapy— thebook.Everyuserisrequestedtoexamine Handbooks.5.PharmaceuticalPreparations— carefully the manufacturers’ leaflets accom- Atlases.6.PharmaceuticalPreparations—Hand- panying each drug and to check, if necessary books.QV17T197c2005a]I.Lüllmann,Heinz. in consultation with a physician or specialist, II.Title. whether the dosage schedules mentioned therein or the contraindications statedby the RM301.12.T38132005 manufacturersdifferfromthestatementsmade 615’.1—dc22 in thepresentbook.Suchexaminationispar- 2005012554 ticularly important with drugs that are either rarelyusedorhavebeennewlyreleasedonthe Translator:DetlefBieger,M.D. market.Everydosagescheduleoreveryformof applicationusedisentirelyattheuser’sownrisk Illustrator:JürgenWirth,ProfessorofVisual and responsibility. The authors and publishers Communication,UniversityofAppliedSciences, requesteveryuser toreporttothepublishers Darmstadt,Germany anydiscrepanciesorinaccuraciesnoticed. Someoftheproductnames,patents,andregis- tereddesignsreferredtointhisbookareinfact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance ofa name without designation as proprietaryisnottobeconstruedasarepre- sentationbythepublisherthatitisinthepublic ©2005GeorgThiemeVerlag, domain. Rüdigerstrasse14,70469Stuttgart,Germany http://www.thieme.de ThiemeNewYork,333SeventhAvenue, NewYork,NY10001USA http://www.thieme.com Thisbook,includingallpartsthereof,islegally protectedbycopyright.Anyuse,exploitation,or Coverdesign:Cyclus,Stuttgart commercializationoutsidethenarrowlimitsset TypesettingbyprimustypeHurlerGmbH, bycopyrightlegislation,withoutthepublisher’s Notzingen consent,isillegalandliabletoprosecution.This PrintedinGermanybyAppl,Wemding appliesinparticulartophotostatreproduction, copying,mimeographing,preparationofmicro- ISBN 3-13-781703-X(GTV) films,andelectronicdataprocessingandstor- ISBN1-58890-332-X(TNY) age. V Preface to the 3rd edition In many countries, medicine is at present Astheneweditionwasnearingcompletion, facing urgent political and economic calls severalhigh-profiledrugsexperiencedwith- for reform. These socioeconomic pressures drawalfromthemarket,substantivechange notwithstanding, pharmacotherapy has al- inlabeling,orclassactionlitigationagainst waysbeenanintegralpartofthehealthcare theirmanufacturers.Amidgrowingconcern system and will remain so in the future. overeffectivenessofdrugsafetyregulations, Well-foundedknowledgeofthepreventive “pharmacovigilance” has become a new andtherapeuticvalueofdrugsisasinequa priority. It is hoped that this compendium nonforthesuccessfultreatmentofpatients mayaidinpromotingthecriticalawareness entrusting themselves to a physician or andrationalattituderequiredtomeetthat pharmacist. demand. Becauseoftheplethoraofproprietarymed- Wearegratefulforcommentsandsugges- icines and the continuous influx of new tions from colleagues, and from students, pharmaceuticals,thedrugmarketisdif cult both doctoral and undergraduate. Thanks to survey and hard to understand. This is areduetoProfessorR.Lüllmann-Rauchfor truenotonlyforthestudentinsearchofa histological and cell-biological advice. We logicalsystemfordealingwiththewealthof are indebted to Ms. M. Mauch and Ms. K. available drugs, but also for the practicing Jürgens, Thieme Verlag, for their care and clinicianinimmediateneedofindependent assistanceandtoMs.GabrieleKuhnforhar- information. moniouseditorialguidance. Clearly, a pocket atlas can provide only a HeinzLüllmann,Kiel basic framework. Comprehensive knowl- KlausMohr,Bonn edgehastobegainedfrommajortextbooks. LutzHein,Freiburg Asisevidentfromthedruglistsincludedin DetlefBieger,St.John’s,Canada theAppendix,some600drugsarecovered JürgenWirth,Darmstadt inthepresentAtlas.Thisnumbershouldbe suf cientforeverydaymedicalpracticeand could be interpreted as a Model List. The Disclosure:TheauthorsoftheColorAtlasof advances in pharmacotherapy made in re- Pharmacologyhavenofinancialinterestsor centyearshave requiredustoincorporate otherrelationshipsthatwouldinfluencethe new plates and text passages, and to ex- contentofthisbook. punge obsolete approaches. Several plates needed to be brought in line with new knowledge. VI Contents Contents General Pharmacology 1 HistoryofPharmacology. . . . . . . . 2 DrugMetabolismbyCytochrome P450. . . . . . . . . . . . . . . . . . . . 38 TheIdea . . . . . . . . . . . . . . . . 2 TheKidneyasanExcretoryOrgan . . . 40 TheImpetus. . . . . . . . . . . . . . 2 PresystemicElimination. . . . . . . . . 42 EarlyBeginnings. . . . . . . . . . . . 3 Foundation. . . . . . . . . . . . . . . 3 Pharmacokinetics . . . . . . . . . . . . 44 Consolidation—GeneralRecognition. 3 StatusQuo. . . . . . . . . . . . . . . 3 DrugConcentrationintheBodyas aFunctionofTime—FirstOrder DrugSources . . . . . . . . . . . . . . 4 (Exponential)RateProcesses . . . . . . 44 TimeCourseofDrugConcentration DrugandActivePrinciple. . . . . . . . 4 inPlasma . . . . . . . . . . . . . . . . . 46 TheAimsofIsolatingActive TimeCourseofDrugPlasmaLevels Principles. . . . . . . . . . . . . . . . . 4 duringRepeatedDosing(A). . . . . . . 48 EuropeanPlantsasSourcesof TimeCourseofDrugPlasmaLevels EffectiveMedicines . . . . . . . . . . . 6 duringIrregularIntake(B). . . . . . . . 48 Accumulation:Dose,DoseInterval, DrugDevelopment . . . . . . . . . . . 8 andPlasmaLevelFluctuation(A). . . . 50 CongenericDrugsandName ChangeinEliminationCharacteristics Diversity . . . . . . . . . . . . . . . . . 10 duringDrugTherapy(B). . . . . . . . . 50 DrugAdministration . . . . . . . . . . 12 QuantificationofDrugAction. . . . . 52 OralDosageForms. . . . . . . . . . . . 12 Dose–ResponseRelationship . . . . . . 52 DrugAdministrationbyInhalation. . . 14 Concentration–EffectRelationship(A). 54 DermatologicalAgents . . . . . . . . . 16 Concentration–EffectCurves(B) . . . . 54 SkinProtection(A). . . . . . . . . . . . 16 DermatologicalAgentsasVehicles(B). 16 Drug–ReceptorInteraction. . . . . . . 56 FromApplicationtoDistributionin Concentration–BindingCurves . . . . . 56 theBody . . . . . . . . . . . . . . . . . 18 TypesofBindingForces . . . . . . . . . 58 CovalentBonding . . . . . . . . . . . 58 CellularSitesofAction. . . . . . . . . 20 NoncovalentBonding . . . . . . . . . 58 PotentialTargetsofDrugAction. . . . 20 Agonists—Antagonists. . . . . . . . . . 60 ModelsoftheMolecularMechanism DistributionintheBody. . . . . . . . 22 ofAgonist/AntagonistAction(A). . . . 60 OtherFormsofAntagonism. . . . . . . 60 ExternalBarriersoftheBody. . . . . . 22 EnantioselectivityofDrugAction. . . . 62 Blood–TissueBarriers . . . . . . . . . . 24 ReceptorTypes. . . . . . . . . . . . . . 64 MembranePermeation . . . . . . . . . 26 ModeofOperationofG-Protein- PossibleModesofDrugDistribution. . 28 coupledReceptors. . . . . . . . . . . . 66 BindingtoPlasmaProteins. . . . . . . 30 TimeCourseofPlasmaConcentration andEffect. . . . . . . . . . . . . . . . . 68 DrugElimination . . . . . . . . . . . . 32 TheLiverasanExcretoryOrgan . . . . 32 AdverseDrugEffects . . . . . . . . . . 70 BiotransformationofDrugs. . . . . . . 34 UndesirableDrugEffects,Side Effects. . . . . . . . . . . . . . . . . . . 70 Contents VII CausesofAdverseEffects. . . . . . . . 70 GeneticVariationofDrugEffects. . . 78 DrugAllergy . . . . . . . . . . . . . . . 72 Pharmacogenetics . . . . . . . . . . . . 78 CutaneousReactions . . . . . . . . . . 74 DrugToxicityinPregnancyand Drug-independentEffects . . . . . . . 80 Lactation . . . . . . . . . . . . . . . . . 76 Placebo(A) . . . . . . . . . . . . . . . . 80 Systems Pharmacology 83 DrugsActingontheSympathetic Vasodilators . . . . . . . . . . . . . . . 122 NervousSystem. . . . . . . . . . . . . 84 Vasodilators—Overview . . . . . . . . . 122 SympatheticNervousSystem. . . . . . 84 OrganicNitrates . . . . . . . . . . . . . 124 StructureoftheSympathetic CalciumAntagonists. . . . . . . . . . . 126 NervousSystem . . . . . . . . . . . . . 86 I.DihydropyridineDerivatives. . . . . . 126 AdrenergicSynapse . . . . . . . . . . . 86 II.VerapamilandOtherCatamphiphilic AdrenoceptorSubtypesand Ca2+Antagonists. . . . . . . . . . . . . 126 CatecholamineActions . . . . . . . . . 88 SmoothMuscleEffects . . . . . . . . . 88 InhibitorsoftheRenin–Angiotensin– Cardiostimulation . . . . . . . . . . . . 88 AldosteroneSystem. . . . . . . . . . . 128 MetabolicEffects. . . . . . . . . . . . . 88 ACEInhibitors. . . . . . . . . . . . . . . 128 Structure–ActivityRelationships ofSympathomimetics. . . . . . . . . . 90 DrugsActingonSmoothMuscle . . . 130 IndirectSympathomimetics. . . . . . . 92 α-Sympathomimetics, DrugsUsedtoInfluenceSmooth α-Sympatholytics . . . . . . . . . . . . 94 MuscleOrgans . . . . . . . . . . . . . . 130 β-Sympatholytics(β-Blockers) . . . . . 96 Typesofβ-Blockers . . . . . . . . . . . 98 CardiacDrugs . . . . . . . . . . . . . . 132 Antiadrenergics . . . . . . . . . . . . . 100 CardiacGlycosides . . . . . . . . . . . . 134 AntiarrhythmicDrugs . . . . . . . . . . 136 DrugsActingontheParasympathetic I.DrugsforSelectiveControlof NervousSystem. . . . . . . . . . . . . 102 SinoatrialandAVNodes. . . . . . . . 136 ParasympatheticNervousSystem . . . 102 II.NonspecificDrugActionson CholinergicSynapse. . . . . . . . . . . 104 ImpulseGenerationandPropagation 136 Parasympathomimetics. . . . . . . . . 106 ElectrophysiologicalActionsof Parasympatholytics . . . . . . . . . . . 108 AntiarrhythmicsoftheNa+-Channel BlockingType. . . . . . . . . . . . . . . 138 Nicotine. . . . . . . . . . . . . . . . . . 112 Antianemics . . . . . . . . . . . . . . . 140 ActionsofNicotine . . . . . . . . . . . 112 LocalizationofNicotinicACh DrugsfortheTreatmentofAnemias. . 140 Receptors. . . . . . . . . . . . . . . . . 112 Erythropoiesis(A) . . . . . . . . . . . 140 EffectsofNicotineonBodyFunction . 112 VitaminB (B) . . . . . . . . . . . . 140 12 AidsforSmokingCessation. . . . . . . 112 FolicAcid(B). . . . . . . . . . . . . . 140 ConsequencesofTobaccoSmoking . . 114 IronCompounds . . . . . . . . . . . . . 142 BiogenicAmines. . . . . . . . . . . . . 116 Antithrombotics. . . . . . . . . . . . . 144 Dopamine. . . . . . . . . . . . . . . . . 116 ProphylaxisandTherapyofThromboses144 HistamineEffectsandTheir VitaminKAntagonistsandVitaminK . 146 PharmacologicalProperties. . . . . . . 118 PossibilitiesforInterference(B). . . . . 146 Serotonin. . . . . . . . . . . . . . . . . 120 Heparin(A) . . . . . . . . . . . . . . . . 148 VIII Contents HirudinandDerivatives(B). . . . . . . 148 DepolarizingMuscleRelaxants . . . . . 186 Fibrinolytics. . . . . . . . . . . . . . . . 150 AntiparkinsonianDrugs . . . . . . . . . 188 Intra-arterialThrombus Antiepileptics. . . . . . . . . . . . . . . 190 Formation(A) . . . . . . . . . . . . . . 152 Formation,Activation,and DrugsfortheSuppressionofPain . . 194 AggregationofPlatelets(B). . . . . . . 152 InhibitorsofPlatelet PainMechanismsandPathways . . . . 194 Aggregation(A) . . . . . . . . . . . . . 154 PresystemicEffectofASA. . . . . . . . 154 AntipyreticAnalgesics . . . . . . . . . 196 Eicosanoids . . . . . . . . . . . . . . . . 196 PlasmaVolumeExpanders. . . . . . . 156 AntipyreticAnalgesicsvs.NSAIDs. . . . 198 NonsteroidalAnti-inflammatory DrugsUsedinHyperlipoproteinemias 158 Drugs(NSAIDs). . . . . . . . . . . . . . 198 Lipid-loweringAgents. . . . . . . . . . 158 NonsteroidalAnti-inflammatory Diuretics . . . . . . . . . . . . . . . . . 162 Drugs . . . . . . . . . . . . . . . . . . . 200 Diuretics—AnOverview . . . . . . . . . 162 Cyclooxygenase(COX)Inhibitors. . . . 200 NaClReabsorptionintheKidney(A). . 164 Aquaporins(AQP) . . . . . . . . . . . . 164 LocalAnesthetics . . . . . . . . . . . . 202 OsmoticDiuretics(B) . . . . . . . . . . 164 DiureticsoftheSulfonamideType. . . 166 Opioids . . . . . . . . . . . . . . . . . . 208 Potassium-sparingDiureticsand OpioidAnalgesics—MorphineType. . . 208 Vasopressin. . . . . . . . . . . . . . . . 168 Potassium-sparingDiuretics(A) . . . . 168 VasopressinandDerivatives(B) . . . . 168 GeneralAnesthetics. . . . . . . . . . . 214 GeneralAnesthesiaandGeneral DrugsfortheTreatmentofPeptic AnestheticDrugs. . . . . . . . . . . . . 214 Ulcers. . . . . . . . . . . . . . . . . . . 170 InhalationalAnesthetics. . . . . . . . . 216 InjectableAnesthetics . . . . . . . . . . 218 DrugsforGastricandDuodenal Ulcers. . . . . . . . . . . . . . . . . . . 170 I.LoweringofAcidConcentration. . 170 Psychopharmacologicals . . . . . . . . 220 II.ProtectiveDrugs . . . . . . . . . . 172 Sedatives,Hypnotics. . . . . . . . . . . 220 III.EradicationofHelicobacter Benzodiazepines . . . . . . . . . . . . . 222 pylori(C). . . . . . . . . . . . . . . . 172 BenzodiazepineAntagonist. . . . . . 222 PharmacokineticsofBenzodiazepines . 224 Laxatives. . . . . . . . . . . . . . . . . 174 TherapyofDepressiveIllness . . . . . . 226 Mania . . . . . . . . . . . . . . . . . . . 230 1.BulkLaxatives. . . . . . . . . . . . 174 TherapyofSchizophrenia . . . . . . . . 232 2.IrritantLaxatives . . . . . . . . . . 176 Neuroleptics . . . . . . . . . . . . . . 232 2a.Small-BowelIrritantPurgative. . 178 Psychotomimetics(Psychedelics, 2b.Large-BowelIrritantPurgatives . 178 Hallucinogens) . . . . . . . . . . . . . . 236 3.Lubricantlaxatives . . . . . . . . . 178 Hormones. . . . . . . . . . . . . . . . . 238 Antidiarrheals . . . . . . . . . . . . . . 180 HypothalamicandHypophyseal AntidiarrhealAgents. . . . . . . . . . . 180 Hormones. . . . . . . . . . . . . . . . . 238 ThyroidHormoneTherapy. . . . . . . . 240 DrugsActingontheMotorSystem . 182 HyperthyroidismandAntithyroid DrugsAffectingMotorFunction . . . . 182 Drugs . . . . . . . . . . . . . . . . . . . 242 MuscleRelaxants. . . . . . . . . . . . . 184 GlucocorticoidTherapy . . . . . . . . . 244 NondepolarizingMuscleRelaxants. . . 184 I.ReplacementTherapy . . . . . . . . . 244 Contents IX II.PharmacodynamicTherapywith AntifungalDrugs . . . . . . . . . . . . 284 Glucocorticoids(A) . . . . . . . . . . . 244 DrugsUsedintheTreatmentof Androgens,AnabolicSteroids, FungalInfections. . . . . . . . . . . . . 284 Antiandrogens . . . . . . . . . . . . . . 248 InhibitoryPrinciples. . . . . . . . . . 248 AntiviralDrugs. . . . . . . . . . . . . . 286 FollicularGrowthandOvulation, EstrogenandProgestinProduction . . 250 ChemotherapyofViralInfections. . . . 286 OralContraceptives . . . . . . . . . . . 252 DrugsfortheTreatmentofAIDS. . . . 290 AntiestrogenandAntiprogestin I.InhibitorsofReverse ActivePrinciples . . . . . . . . . . . . . 254 Transcriptase—NucleosideAgents . . 290 AromataseInhibitors . . . . . . . . . . 256 NonnucleosideInhibitors . . . . . . . 290 InsulinFormulations. . . . . . . . . . . 258 II.HIVproteaseInhibitors. . . . . . . 290 VariationsinDosageForm. . . . . . 258 III.FusionInhibitors . . . . . . . . . . 290 VariationinAminoAcidSequence. . 258 TreatmentofInsulin-dependent AntiparasiticDrugs . . . . . . . . . . . 292 DiabetesMellitus. . . . . . . . . . . . . 260 DrugsforTreatingEndoparasitic UndesirableEffects . . . . . . . . . . 260 andEctoparasiticInfestations. . . . . . 292 TreatmentofMaturity-Onset Antimalarials . . . . . . . . . . . . . . . 294 (TypeII)DiabetesMellitus. . . . . . . . 262 OtherTropicalDiseases . . . . . . . . . 296 OralAntidiabetics . . . . . . . . . . . . 264 DrugsforMaintainingCalcium AnticancerDrugs . . . . . . . . . . . . 298 Homeostasis . . . . . . . . . . . . . . . 266 ChemotherapyofMalignant AntibacterialDrugs. . . . . . . . . . . 268 Tumors . . . . . . . . . . . . . . . . . . 298 TargetingofAntineoplasticDrug DrugsforTreatingBacterial Action(A). . . . . . . . . . . . . . . . . 302 Infections. . . . . . . . . . . . . . . . . 268 MechanismsofResistanceto InhibitorsofCellWallSynthesis . . . . 270 Cytostatics(B) . . . . . . . . . . . . . . 302 InhibitorsofTetrahydrofolate Synthesis . . . . . . . . . . . . . . . . . 274 ImmuneModulators . . . . . . . . . . 304 InhibitorsofDNAFunction . . . . . . . 276 InhibitorsofProteinSynthesis . . . . . 278 InhibitionofImmuneResponses . . . . 304 DrugsforTreatingMycobacterial Infections. . . . . . . . . . . . . . . . . 282 Antidotes. . . . . . . . . . . . . . . . . 308 Antituberculardrugs(1) . . . . . . . 282 AntidotesandTreatmentof Antileproticdrugs(2). . . . . . . . . 282 Poisonings. . . . . . . . . . . . . . . . . 308 Therapy of Selected Diseases 313 Hypertension. . . . . . . . . . . . . . . 314 Osteoporosis . . . . . . . . . . . . . . . 330 AnginaPectoris . . . . . . . . . . . . . 316 RheumatoidArthritis. . . . . . . . . . . 332 AntianginalDrugs . . . . . . . . . . . . 318 Migraine. . . . . . . . . . . . . . . . . . 334 AcuteCoronarySyndrome— CommonCold . . . . . . . . . . . . . . 336 MyocardialInfarction . . . . . . . . . . 320 AtopyandAntiallergicTherapy. . . . . 338 CongestiveHeartFailure . . . . . . . . 322 BronchialAsthma. . . . . . . . . . . . . 340 Hypotension . . . . . . . . . . . . . . . 324 Emesis. . . . . . . . . . . . . . . . . . . 342 Gout. . . . . . . . . . . . . . . . . . . . 326 AlcoholAbuse. . . . . . . . . . . . . . . 344 Obesity—Sequelaeand LocalTreatmentofGlaucoma. . . . . . 346 TherapeuticApproaches. . . . . . . . . 328 X Contents Further Reading 349 Drug Indexes 351 TradeName–DrugName . . . . . . . 352 DrugName–TradeName. . . . . . . . 369 Subject Index 381