Table Of Content

At a glance General Pharmacology Systems Pharmacology Ther.~py of Selected Diseases Further Reading Glossary Dn~g Index Abbreviations Subject Index (!)Thieme Color Atlas of Pharmacology Fifth Edition t Heinz Luellmann, MD Fonner Professor and Otairman Department of Pharmacology University of Kiel Kiel, Germany Klaus Mohr, MD Professor Institute of Pharmacy Section of Pharmacology and Toxicology University of Bonn Bonn, Germany Lutz Hein, MD Professor Institute of Experimental and Clinical Pharmacology and Toxicology University of Preiburg Freiburg, Germany With 174 color plates by Juergen Wirth Thieme Stuttgart • New York • Delhi • Rio de janeiro Ubmy ttl Clmgreu c.aaaJaclng-bl-l'ublladlm Data lmpoJtallt n0111: Medldne Is an --dlanalna sd Is aw!WJ~t from die pubi!Jher. ence lll!detping amdruul develop~~~tU. ~ 'CGIbaeioms1 azb .oTnoh ekide Imisti eoa nV.n ep aruluab&dlil soShr1ieJ:diue itdlJp Jtrdrra .C nOsUIItYlorinlh toSl 2ti0l1e5 7 bdyl i~treJalmJedfttc i JI:Jnd tp dairrutigD0 1tihIaerQr aopIuyr. ~ kIn-nso~~fPa~rN u~0 1oChr 1ips mb1apo'eJcr l1tle of! he Cemwl edition: ~u mendons ~eyllosage or ~n, readenmayrest l'hinllalaololie ~thatlheillllhon,tdilxn,illdpublisba$~ Baude m~ Clfi&IMill'allsUifmtb yD elfe¥ lllept', MD. made eve!)' eftbrt I:D* CI IJIUI! that sud!~*~ Im~JMIIOusls'lllt aWnlm\slnr l.f D ll.Pr lfr ltbrvhaflei.nn JkS.uIfRtuehrir atEs,nm cGdll deW armnir atthrna.yn D sllitlaekd hb.y GGeerrmaldaninye; It~inm iNCeIe CoYIfI eIp ~drarelhnnyecd gelueu wada,ri laattmbaim ellle fd toha~ree r sbe utnpooOokDt.s l!bnflvlol~lwy~ o, nI md pi•el y p, aDnr Gfd!epublisb=in~I:Dany~inslnlctilms 1st Albanim edition 2005 and lbrmt ola ppllatkms stalled In the baok. 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Hary;ma 54321 ISBN9711-3-ll-241065-7 Aim avallabl.l! as an Hlcok; eJSBN 978..3-13-241143-2 Contents General Pharmacology History of Pharmacology.................................................. 14 1,1 HistoryofPh;um;~tology ...... 14 2 Drug Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 2.1 Drug and Active Principle . . . . . . 16 2A Drug Development . . . . . . . . . . . . 22 2.2 Plants as Sou ~US of Effective 2.5 Drug Benefit Assessment . . . . . . 24 Meclldnes . . . . . . . . . . . . . . . . . . . . . 18 2.6 Congenerk Drugs and Name 2.3 Human Proteins as Medicines . . 20 Diversity . . . . . . . . . . . . . . . . . . . . . . 26 3 Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 3.1 Oral Dosage Fonns . . . . . . . . . . . . 28 3.3 Dennatological Agents . . . . . . . . 32 3.2 Drug Administration by lA Distribution in the Body . . . . . . . 34 lnhalatfon . . . . . . . . . . . . . . . . . . . . . 30 4 Cellular Sites of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.1 Targets of Drug Actfon . . . . . . . . 36 5 Distribution In the Body. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 5.1 Extemal Barriers of the Body . . 38 5.5 Distribution of Drugs . . . . . . . . . . 46 5.2 Blood-Tissue Barriers. . . . . . . . . . 40 5.6 Binding of Drugs to Plasma 5.3 Membrane Permeation . . . . . . . . 42 Proteins . . . . . . . . . . . . . . . . . . . . . . . 48 5.4 Drug Transporters . . . . . . . . . . . . . 44 6 Drug Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 6.1 The Uver as an Excretory 6.4 Enterohepatlc arculatlon . . . . . . 56 Organ . . . . . . . . . . . . . . . . . . . . . . . . . 50 6.5 The Kidney as an Excretory 6.2 Biotransformation of Drugs. . . . 52 Organ . . . . . . . . . . . . . . . . . . . . . . . . . 58 6.3 Drug Metabolism by CYP . . . . . . 54 6.6 Presystemic Elimination . . . . . . . 60 7 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 7.1 Drug Concentration In the 7.3 Time Course during Repeated Body .......................... 62 Dosing ........................ 66 7.2 Time Course of Drug 7 A Accumulation . . . . . . . . . . . . . . . . . 68 Concentration . . . . . . . . . . . . . . . . . 64 8 Quantification of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 8.1 Dose-Response Relationship . . 70 8.3 Concentration-Binding 8.2 Concentration-Effect Curves ........................ 74 Relationship . . . . . . . . . . . . . . . . . . . 72 9 Drug-Receptor Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 9.1 Types of Binding FoKeS . . . . . . . . 76 9.3 EnantloselectMty of Drug 9.2 Agonlsts-Antagonlsts . . . . . . . . . 78 Action . . . . . . . . . . . . . . . . . . . . . . . . . 80 5 Contents 9.4 Receptor Types . . . . . . . . . . . . . . . . 82 9.6 Plasma Concentration and 9.5 G-Protein-coupled Receptors . . 84 Effect . . . . . . . . . . . . . . . . . . . . . . . . . . 86 1 0 Adverse Drug Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 10.1 Adverse Drug Effects: Causes . . 88 1 OA Pregnancy and Lactation . . . . . . 94 10.2 Drug Allergy ................... 90 10.5 Cienetk Variation of Drug 10.3 Cutaneous Reactions . .. . .. . .. . 92 Effects......................... 96 11 Drug-Independent Effects . .. . . .. . .. . .. . . .. . .. .. .. . .. .. .. . .. . . . . .. . . .. . .. . . 98 11.1 Placebo Therapy .. . . .. . .. . .. . .. 98 Systems Pharmacology 12 Sympathetic Nervous System............................................ 102 12.1 Function of the Sympathetic 12A Sympathomimetics.......... 110 System ...................... 102 12.5 lndiredSympathomimetics .. 112 12.2 Structure of the Sympathetic 12.6 o-Sympathomimetia, Nervous System .. . .. . .. . .. .. 104 o-Sympatholytia............ 114 12.3 Adrenoceptor Subtypes and 12.7 P·Sympatholytia Catecholamine Adlons .. .. .. 106 (P.blockers) . .. .. . .. . .. . .. . .. 116 13 Parasympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 13.1 Parasympathetic Functions .. 118 13.3 Parasympathomlmetla .. . .. 122 13.2 Cholinergic Synapse . .. . .. .. . 120 13A Parasympatholytla.......... 124 14 Biogenic Amlnes.......................................................... 128 14.1 Dopamine................... 128 14A Substance Pand Amino 14.2 Histamine................... 130 Acids........................ 134 14.3 Serotonin ... .. ... ... . .. .... . 132 15 Vasodilators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 15.1 Vasodilators-Overview . .. .. 136 15.3 CaldumAntagonlsts... .... .. 140 15.2 Organic Nitrates . .. .. . .. .. .. . 138 16 Inhibitors of the Renin-Angiotensin-Aldosterone System . .. . .. . . . . . . . . 142 16.1 ACE Inhibitors .. .. . .. . .. . .. .. 142 17 Drugs Acting on Smooth Muscle . .. . . .. . .. . . . .. .. . . .. . .. . . .. . .. . .. . .. . . .. 144 17.1 Drugs Acting on Smooth Musde ...................... 144 18 (ardlac Drugs .. . .. . . .. . .. . .. . . .. . .. . . .. . .. . .. . . .. . ... . .. . .. . . . . ... . .. . .. . 146 18.1 Cardiac Drugs--{)vervfew.... 146 18.3 AnUarrhythmlc Drugs .. .. . .. 150 18.2 Cardiac Cilycosldes........... 148 19 Antianemic Agents ....................................................... 154 19.1 Treatment of Anemias ....... 154 19.2 lronCompounds ............. 156 6 Contents 20 AntlthrombotlcAgents... .. . . .. . .. . ... . .. . .. . . .. . .. . . .. . . .. . .. . .. . ... . .. . 158 20.1 Thrombosis Therapy......... 158 20.4 Fibrinolytics .. . .. . . .. . .. . . .. . 164 20.2 VItamin K Antagonists and 20.5 Inhibitors of Platelet VItamin K ... ... ... ... .. ... .. 160 Aggregation................. 166 20.3 Heparin .. ... .. .. ... .. .. ... .. 162 21 Plasma Volume Expanders . . . .. . .. . . .. . .. . .. . . .. . . .. . .. . . .. . .. . . .. . .. . .. . 168 21.1 Plasma Volume Expanders . . . 168 22 Drugs Used in Hyperlipoproteinemias . .. . .. . . .. . . .. . .. . . .. . .. . . .. . .. . .. . 170 22.1 Llpld-lowertng Agents . . . . . . . 170 23 Diuretics . .. . . .. . .. . . .. . .. . .. . . .. . .. . .. . . .. . .. . . .. . .. . . .. . . .. . .. . .. . . .. . .. . 174 23.1 Dluretlcs-Ovenlfew .. .. .. .. . 174 23.3 Diuretics of the Sulfonamide 23.2 NaCI and Water Reabsorption Type . .. .. . .. . .. .. .. .. . .. .. . .. 178 In the Kidney . . . . . . . . . . . . . . . . 176 23.4 Potasslum-5paring Diuretics and Vasopressin .. . .. . .. . .. .. 180 24 Water and Electrolyte Disorders .. . . .. . .. .. .. .. .. . .. . .. . .. .. .. . . .. . .. . . .. 182 24.1 Water and Electrolyte Disorders . .. . . .. . .. . . .. . .. . .. 182 25 Gastrointestinal Tract . .. . .. . . .. . .. . ... . .. . .. . . .. . .. . . .. . . .. . .. . .. . . .. . .. . 184 25.1 Treabnent of Hyperacidity, 25.2 Antidiarrheal Agents . . . . . . . . 188 Use of Lmratives • .. .. .. . .. . .. 184 26 Drugs Affecting the Motor System . .. . . .. . .. . . .. . .. . . .. . . .. . .. . .. . . .. . .. . 190 26.1 MotorSystem ............... 190 26.2 Muscle Relaxants ............ 192 27 Drugs for the Suppression of Pain (Analgesics) . . . . . . . . . . . . . . . . . . . . . . . . . . 196 27.1 Nociceptors and Pain 27.3 Antipyretic Analgesics . . . . . . . 200 P01thWiiY5 .................... 196 27.4 LotiiiAnesthetics ............ 204 27.2 Eicosanoids.................. 198 27.5 Opioids...................... 210 28 Drugs Acting on the Central Nervous System............................ 216 28.1 General Anesthesia and General 28.5 Pharmacokinetics of Anesthetic Drugs .. .. .. .. .. .. 216 Benzodlazeplnes............. 224 28.2 lnhalatlonal Anesthetics . . . . . 218 28.6 Therapy of Depressive 28.3 Injectable Anesthetics .. .. . .. 220 Illness . .. . .. . .. . .. . .. . .. .. . .. 226 28.4 Anxlolytlcs .................. 222 28.7 TherapyofManlcStates ..... 230 28.8 Therapy of Schizophrenia . . . . 232 29 Drugs Affecting the Endocrine System . .. . .. . .. . . .. . .. . . . .. . . . . .. . .. . . .. . 236 29.1 Hypothalamic and Hypophyseal 29.4 Glucocortkold Therapy . . . . . . 242 Hormones . . . . . . . . . . . . . . . . . . . 236 29.5 Androgens, Anabolic Steroids, 29.2 Thyroid Honnone Therapy . . . 238 Antlandrogens . . . . . . . . . . . . . . 246 29.3 Hyperthyroidism and 29.6 Follicular Growth and Antithyroid Drugs . .. . .. . .. .. 240 Owlation .. . .. . .. . .. . .. .. . .. 248 7 Contents 29.7 Oral Contraceptives . . . . . . . . . 250 29.11 Treatment of Diabetes 29.8 Antiestrogen and Antiprogestin Mellitus . . . . . . . .. .. .. .. . .. . . . 258 Active Prindples . . .. . . .. . .. . . 252 29.12 Type II Diabetes Mellitus . . . . . 260 29.9 Aromatase Inhibitors . . . . . . . . 254 29.13 Oral Antidiabetic Drugs. . . . . . 262 29.1 0 Insulin Formulations. . . . . . . . . 256 29.14 Maintaining Caldum Homeostasis . . . .. . .. .. . .. . . . 264 30 Antibacterial Drugs .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 30.1 Drugs for Treating Bacterial 30.4 Inhibitors of DNA Function . . 274 Infections . . . . . . . . . . . . . . . . . . . 266 30.5 Inhibitors of Protein 30.2 Inhibitors of Cell Wall Synthesis . . . . . . . . . . . . . . . . . . . . 276 Synthesis .. .. .. . .. . . .. . . . . . .. 268 30.6 Drugs for Treating 30.3 Pore Formers and Inhibitors Mycobacterial Infections. . . . . 280 of THF Synthesis .. . .. . . .. . .. . 272 31 Antifungal Drugs . . . . . . . .. . . . . . . . . . . . . .. . .. . .. . . . . . . . . . .. . .. . .. . . . . . . . . . . . 282 31.1 Drugs Used In the Treatment of Fungallnfections .. .. . . . . . . . . 282 32 Antiviral Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 32.1 Pharmacotherapy of VIral 32.2 Drugs for the Treatment Infections . . . . . . . . . . . . .. . .. . . 284 of HIV . .. . .. . .. . . . . . . . . . .. . .. 288 33 Antiparasitic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . . 290 33.1 Endo-and Ectoparasltes . . . . . 290 34 Tropical Diseases .. . .. . . .. . .. . . .. . .. . . .. . .. . .. . . .. . .. . . .. . .. . . . . . .. . .. . .. . 292 34.1 Antimalarial Drugs . . . . . . . . . . 292 34.2 Other Tropical Diseases . . . . . . 294 35 Anticancer Drugs . .. . .. . .. . . .. . .. . .. . . .. . .. . . .. . .. . . .. . .. . . .. . . . . .. . .. . . .. 296 35.1 Cytostatlcs . . . . . . . . . . . . . . . . . . 296 35.3 Special Antineoplastic Drug 35.2 Interference with Cell Actions . . . . . . . . . . . . . . . . . . . . . . 302 Proliferation Signaling Pathways . . . . . . . . . . . . . . . . . . . . 300 36 Immune Modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 36.1 Inhibition of Immune 36.2 Caldneurln Inhibitors, Responses . . . . . . . . . . . . . . . .. . . 304 Sirolimus . .. . . . . . . . . . . . . . . . . . 306 37 Antidotes . .. . .. . . . . . .. . . . . . . . . . . . . . . . . . . . . . . .. . . .. . .. .. .. . .. . . . . . .. . .. . .. . 308 37.1 Antidotes and Treatment of Poisoning . .. . .. . . .. . .. . . .. . . 308 38 •Recreational" Drugs.. . .. . .. . . .. . .. . . .. . .. . . .. . .. . . .. . .. . . .. . . . . .. . .. . .. . 312 38.1 Psychotomlmetlcs........... 312 38.3 Consequences ofTobaao 38.2 Tobacco and Nlcotfne .. .. .. .. 314 Smoking .. . .. . .. . .. .. .. . .. .. 316 38.4 Alcohol Abuse . .. .. . . .. . .. . . . 318 8