Index

Note: Page numbers in bold refer to a text discussion of the entry

abatacept, 636, 695 release cotransmitters, 497 acquired immuno deficiency syndrome abciximab (ReoPro), 233 synthesis and metabolism, 498–501 (AIDS), 3, 387, 414, 542, ABC transporters, 263 vesicles, 500 590–591, 638, 659, 678–9 polymorphisms, 263 acetylcholine receptors, 501–4 HIV infection, 382, 659 substrates, 263 muscarinic (mAChR), 189, 321, acrylamide derivatives, 335 absorption, 21, 31–44 339, 360, 478, 486, 498, action potential, 468 rate, 39, 74 503, 524, 604 activator protein 1 (AP-1), 630 time constant, 74 muscarinic agonists acyclovir, 15, 655–6 absorption distribution metabolism and (parasympathomimetics), Acyl-CoA-cholesterol-acyltransferase elimination (ADME), 671, 695, 504, 506–7 (ACAT), 448 700–707 muscarinic antagonists inhibitors, 448–9 absorption distribution metabolism (parasympatholytics), 338, 498, adalimumab, 239, 627, 636, 695 excretion and toxicity 504, 506–7 adamantanes, 656–7 (ADMET), 701 muscarinic autoreceptors, 501 adaptation, 42, 118, 121–9, 580, 582, 648 abuse see dependence muscle-type receptor, 503 adaptor protein, 112, 113, 118, 218, 219, acamprosate, 128–9 nicotinic, 112, 126, 140, 179, 180, 182, 231, 434 acarbose, 458, 460 184, 186–7, 504–6 addiction, 7, 122–9, 583, 584 acceptable daily intake (ADI), 669 nicotinic (nAChR), 501–3 adefovir, 659 ACE see angiotensin-converting enzyme nicotinic agonists, 504 adenine nucleotide translocase (ANT), (ACE) nicotinic antagonists, 504 411, 436 acebutol, 325, 492–3 nicotinic autoreceptors, 501 adenosine, 157, 190, 192, 336, 501, aceclidine, 504 COPYRIGHTEDacetylcholinesterase (AChE), 65,MATERIAL 137, 359, 553–64, 656 acetylation, 62, 67, 135 497–8, 507, 692 adenosine deaminase (ADA), 304, 419, 555–6 histone acetyltransferase, 135 inhibitors (AChEIs), 499–500, 505, 526 ADA deficiency syndrome, 563 histone deacetylase, 135 acetylcholine transporters, 360 adenosine diphosphate (ADP), 554–64 acetylcholine (ACh), 190, 194, 496–501, vesicular ACh transporter 1 (VAChT1), adenosine kinase, 556 512, 513, 515 498, 500 adenosine monophosphate (AMP), 555–64 binding protein, 116, 179 acetyl-CoA, 67, 440, 441, 497, 499, 653 adenosine triphosphate (ATP), 190, ganglionic neurotransmission, 479, 503, 506 acetyl-CoA transporter (ACATN), 499 553–64 precursors, 499 acetylprocainamide, 338 adenylate kinase, 555 release, 118, 321, 351, 475, 479, acidification, 56, 161, 169, 355–6, 381, adenylyl cyclase, 195–6 487, 488, 501, 512, 580 475, 684 adesleukin, 638

General and Molecular Pharmacology: Principles of Drug Action, First Edition. Edited by Francesco Clementi and Guido Fumagalli. © 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.

0002534462.indd 714 5/11/2015 2:38:20 PM Index 715

adherent junctions see junctions adrenocorticotrope hormone (ACTH), 190, amisulpride, 517–18 adhesion molecules, 219, 220, 222, 227, 221, 481, 489, 494, 523, 567, amitriptyline, 35, 49, 71, 338, 486, 515, 229, 233, 324, 466, 473, 523, 570, 574 517–18, 682 628, 634, 636 adverse reactions, 7, 36, 259, 262, 290, amoxicillin, 34, 642 adhesive receptors, 225–6 291, 682, 698 AMPA receptors see glutamate receptors drug targeting, 233–4 affinity, 95, 96, 99, 101, 103, 104, 107, 108 amphetamines, 124, 126, 361, 366, 485, 515 adipocytes, 282, 393, 458, 460, 563, 586, agomelatine, 517 3,4-methylenedioxy-N- 609, 619 agonist, 102 ethylamphetamine (MDEA), 515 adrenocorticotropic hormone (ACTH), agonists 3,4-methylenedioxy-N- 190, 221, 481, 489, 494, 523, inverse, 107–8 methylamphetamine (MDMA), 567, 570, 574 partial, 104–5 122, 124, 366, 370, 515 administration routes, 31–43 Agouti-related peptide (ARP), 569 amphotericin B, 651–4, 661 dermal route, 37–8 AIDA, 550 ampicillin, 14, 34, 642, 679, 685 drip injection, 35 AIDS see acquired immuno deficiency amprenavir, 387, 393 drug delivery, 42–3 syndrome (AIDS) anacetrapib, 449–50 drug targeting, 43 A-kinase-anchoring protein (AKAP), 196, 198 anakinra, 628, 636, 695 enteral route, 33 Akt, 169, 170, 413 analgesia, 576–9 inhalation route, 36–7 alanine (β-), 365 anandamide (AEA), 112, 585–7, 587, 593–5 intradermal route, 36 Albright’s hereditary osteodystrophy, 194 anaphylaxis, 492, 573, 629 intramuscular route (i.m.), 36 albumin, 21, 50, 55, 59, 243, 290, 421, androgen receptor, 272, 281 intravascular route (i.v.), 35 614, 681 poly-Q tract polymorphism, 281 mucosal routes, 38 alcohol dehydrogenase, 65, 574 androgens, 272, 281, 283, 672 oral route, 33–5 alcoholism, 574 anesthetics, 12, 21, 31, 33, 37, 94, 319, parenteral routes, 35–6 aldehyde dehydrogenase, 514 321, 323–6, 336, 437, 491, 534, rectal route, 35 aldosterone, 167, 273, 280, 479, 493 540, 549, 567 subcutaneous route, 36 alefacept, 628, 636 general, 336, 534, 536–7, 540 sublingual route, 35 aleglitazar, 448 local, 3, 21, 33, 37, 94, 319, 323–6, 329, systemic administration, 31 alemtuzumab, 239, 628, 636, 695 437, 491 topical/regional routes, 31, 37 alfentanil, 573 angina, 492–3, 602 transcutaneous route, 37–8 alfuzosin, 492 angiotensin-converting enzyme (ACE), adrenal cortex, 280, 386 alkalinization of urine, 56, 169, 684 264, 381, 386, 567 adrenaline, 321, 371–2, 452, 478, 484–5, alkylamines, 527, 651 inhibitors, 15, 42, 264, 347, 349, 386, 492, 685 alkylating agents, 417 679–80 adrenal medulla, 168, 373, 478, 479, 496, allopurinol, 629, 683 angiotensin II, 15, 190, 199–200, 381, 386, 574, 620 allosteric modulators, 102, 103 479, 571, 603, 609 adrenergic and noradrenergic systems, agonist, 103 animal models, 15, 46, 163, 254, 275, 290, 480–481 antagonists, 103 298, 326, 328, 413, 442, 443, control of pituitary functions, 481 potentiators, 103 449, 461, 539, 569, 590, 592, depression, wakefulness and feeding almotriptan, 517 619, 637, 702 behavior, 481 alprazolam, 71, 157, 539, 685 animal testing see toxicity distribution, 480 alteplase, 694–5 antagonists, 102 functions, 480 alternative splicing, 115, 167, 203, 237, competitive, 102 adrenergic receptors, 487 286, 351, 456, 499, 566, 619 insurmountable, 102–3 α-adrenergic receptors, 190, 191, 194, 487 alternatives to animal experiments, 672 surmountable, 102 α1 agonists, 490 Alzheimer’s disease, 169, 505 antazoline, 527 α2 agonists, 491 amanita muscaria, 501 anthracenediones, 416, 423 α antagonists, 491 amantadine, 656 anthracyclines, 416, 422–3, 437, 679 β-adrenergic receptors, 190–192, 194, ambenonium, 500, 505 antiarrhythmic drugs, 320, 338 196, 198–200, 488 amidepsine, 440, 446 class II: β-adrenergic antagonists, 15, β1, 264 amikacin, 642, 647 251, 263, 264, 325, 349, 493 β2, 265 amiloride, 49, 320, 354–6, 399, 557, 600 class III: VGKC blockers, 320, 325 β2 agonists, 491 amineptine, 366 class IV antiarrhythmic: VGCC β antagonists, 15, 251, 263, 264, 325, amine transporters, 360 blockers, 320, 325 349, 493 aminoethyl-hydroxyindole, 509 class I: VGSC blockers, 323, 325 β1 polymorphisms, 264 aminoglycosides, 642–3, 647, 679 antibiotics, 4, 13, 14, 26, 36, 37, 49, 56, β2 polymorphisms, 265 aminopyridine, 147, 320, 336, 505 263, 422, 641–60 drugs and therapeutic use, 490–493 aminopyrine, 612 antineoplastic, 422 functions, 489 amiodarone, 49, 71, 320, 325, 338, 354–5, cytoplasmic membrane function localization, 489 681–3 inhibitors, 649–50

0002534462.indd 715 5/11/2015 2:38:20 PM 716 Index

antibiotics (cont’d ) antiviral drugs, 654–60 association constant, 95 DNA synthesis and replication anti HBV, 659 astemizole, 337–8 inhibitors, 649 anti HCV, 658–9 asthma, 233, 264–5, 280, 290–291, 335, mechanism of action, 642–3 interferons, 659 339–40, 384, 491–3, 506–7, 524, peptidoglycan polymerization NS5B inhibitors, 658 526, 561–4, 570, 573, 600, inhibitors, 645 NS3/4 inhibitors, 658 615–16, 618, 620, 628, 636, 679 peptidoglycan synthesis inhibitors, anti HIV, 659 astrocyte, 362, 369, 466–7, 592, 598, 603 643–5 integrase inhibitors, 660 ataxia telangiectasia, 286 resistance, 650 protease inhibitors, 393 atenolol, 27, 57, 89, 98, 325, 346, 392, ribosomes, 647 reverse transcriptase inhibitors, 659 492, 493 transcription inhibitors, 646 virus entry inhibitors, 660 atorvastatin, 71, 440–441, 450, 685 translation inhibitors, 646–9 anti influenza virus, 656–7 ATP binding cassette, 263, 345, 493 antibodies, 636 mechanism of action, 654–5 atracurium, 504, 506 monoclonal (mAbs), 17, 113, 115, resistance, 656–60 atrial natriuretic peptide, 114 213–15, 233, 239, 417, 427–8, anxiety, 14, 363, 481, 493–4, 511, 517, atropine, 57, 491, 498, 504–8, 680 635, 639, 695 529, 532–4 methylnitrate, 506, 507 monoclonal humanized, 239 Apaf-1, 408, 411 autacoids see specific agents monoclonal therapeutic, 239 apamin, 339 autoimmunity, 626 polyclonal, 635 apolipoproteins, 443, 448, 540 autonomic nervous system, 343, 477–95, anticholinergic agents, 7, 34, 486, 498, apomorphine, 489, 494, 540 553, 609, 619 504, 507, 527, 680 apoptosis, 389, 558, 562–3 avasimibe, 449 antidepressants, 14, 15, 34, 35, 61, 259, regulators, 409 avidity, 48, 52, 81 263, 338, 364, 366, 370–372, apoptosis-inducing factor (AIF), 411 azacytidine (Vidaza), 426 481, 486, 511–12, 515, 515–19 apoptotic bodies, 407 azathioprine, 62, 262, 626–31, 635–6, 679 antidotes, 684 eat me signals, 408 azimilide, 325, 337–8 antiemetics, 65, 263, 338, 517 picnosis, 408 azithromycin, 634, 642, 683–4 antiepileptic drugs, 51, 320, 322–3, 325, apoptotic pathway, 408–11 azoles, 651–4 327, 369, 472, 530, 539 extrinsic pathway, 408, 409 aztreonam, 642 antifungal drugs, 338, 651–4 intrinsic mitochondrial pathway, acting on cytoplasmic membrane, 652–3 408, 411 bacitracin, 642 DNA and protein synthesis apraclonidine, 492 baclofen, 531, 533, 537–40 inhibitors, 653 aprikalim, 335 bacterial toxins, 159–63 mechanism of action, 653 aptamers, 286, 292 Bad, 413, 437 mitotic inhibitors, 653 aquaporin, 339 bafilomycin, 475 resistance, 653 arachidonic acid, 196, 321, 559, 586–7, Bak, 411 antihistamines, 14, 263, 338, 483, 520, 608–20, 634 bamifylline, 561, 563 527, 680, 684 enzymatic metabolism, 610–617 barbiturates, 24, 30, 187, 324, 531–7, 540, antiinflammatory agents, 280, 518, 609, 611 metabolism, 610–617 549, 684 antimalarial drugs, 338, 525–6 non enzymatic metabolism, 617–18 basal ganglia, 51, 481–2, 561–2, 585–6 amodiaquine, 526 release, 609 basiliximab, 239, 628, 636, 695 quinacrine, 526 arachidonoylglycerol (2-AG), 587–8, 595 Batten disease, 303 antimania drugs, 338 area under the plasma concentration curve Bax, 411 antimetabolites, 262, 265, 415, 418–20, 679 (AUC), 74–5 Bcl-2, 148–50, 210, 388, 390, 408, 409, antifolates, 418 arecoline, 504, 507 411, 413, 425, 437 purine analogs, 419 Arf, 154–7 Bcl-XL, 411, 437 pyrimidine analogs, 419, 526 argonaute proteins, 284–6 BCNU, 417 antineoplastic agents, 33, 214, 215, Argonaute2 (AGO2), 285 belladonna alkaloids, 8, 504 415–30 aripiprazole, 516–17 benzamides, 335, 426, 494, 516, 518 conventional antitumor drugs, 33, aromatase, 65 benzimidazoles, 335, 339–40, 351, 444 417–23 aromatic amino acid decarboxylase, 513–14 benzodiazepines, 320, 335, 531–2, 534–5, monoclonal antibodies, 33, 428–9 arrestin (β-), 118, 178, 192, 199–200, 537, 539 target-specific antitumor drugs, 33, 218–20, 581 discovery, 14 423–7 arsenic, 13, 338 benzopyrenes, 335 antioxidants, 437, 439, 618 artemisinin, 353, 581 benzothiadiazines, 335 antipsychotics, 15, 65, 259, 264, 338, aspartate, 178, 205, 346, 361–4, 366, benztropine, 506–7 482–3, 494, 507, 514, 517, 683 379–81, 385, 523, 542, 660 bepridil, 338, 354–5 atypical, 516 aspartate proteases, 381 Bernard, C., 12 typical, 517 aspirin (acetylsalicylic acid, ASA), 4, 24, betaine, 364–9 antipyretics, 611, 638 34, 93, 611–13, 710–711 betaxolol, 325, 492

0002534462.indd 716 5/11/2015 2:38:20 PM Index 717

betazole, 528 bupropion, 71, 128–9, 486 cAMP, 195, 196, 523 bethanechol, 504, 506–7 buspirone, 514, 516–17 cAMP Responsive Element Binding bevacizumab (Avastin), 214, 239, 417, butorphanol, 573 protein (CREB), 245, 251, 427–9 butylscopolamine, 506–7 252–3, 576, 581, 582 bezafibrate, 440 butyrylcholinesterase (BChE), 498–500, camptothecin, 413, 416, 421–2 BH3-only proteins, 410, 411 505–6 canagliflozin, 460–461 HRK, 411 inhibitor N1-phenylethyl-norcymserine, cannabinoid receptors, 585–6, 593–5 NOXA, 411 499 antagonist CB1, 593 PUMA, 411 antagonist/indirect agonist, 594 biased signaling, 108 CAAT box, 246 antagonist/inverse agonist CB1, 593 bicuculline, 531, 533–4, 537, 539 cabozantinib, 214 antagonist/inverse agonist, CB2, 594 Bid, 410, 411 cachexia, 564, 590–591 CB1 receptors (CB1R), 585 tBid, 411 cactus, 124 CB2 receptors (CB2R), 586 biguanide, 459 cadherins, 114, 156, 226, 232, 473 direct agonist CB1/CB2, 593 biliary excretion, 58, 214 signal transduction, 232 direct agonist CB1 selective, 593 biliary secretion, 58 caffeine, 12, 49, 143, 350, 553–4, 557, direct agonist CB2 selective, 593 bilirubin, 51 562–3, 680, 682 GPR55 receptors, 586 bimosiamose (TBC-1269), 233 calcineurin inhibitors, 630 neutral receptor CB2, 594 binding, 97–103 calcitonin, 38, 42, 190, 195, 199, 522, PPARα receptors, 586 experiments, 97 566, 570 cannabinoids, 124, 126, 190, 585–6, 590, sites, 94–9, 102, 103 calcitonin gene related peptide (CGRP), 592–4 studies, 96 516, 566, 567, 570 cannabis sativa, 585, 590–591, 593 Binz, C., 12 calcium (Ca2+), 139–45 capecitabine, 429 bioavailability, 32–3 ATPases, 141 capillary endothelium, 27–8 bioequivalence, 214, 701, 705, 706 binding proteins, 140 captopril, 386–7, 567 bioinformatics, 692, 693 channels, 140–141 carbachol, 504, 506, 507 biological response modifiers (BRMs), 625 diffusion in cytoplasm, 140 carbamazepine, 34, 49, 57, 72, 320, 323, biological target, 692 distribution in cells, 139 325, 679, 682 biotrasformation, 61, 65 in endosomes, 145 carbamic acid, derivatives of, 335 biperiden, 506–7 in the ER, 142 carbapenems, 642 bisoprolol, 492 fluxes in cells, 142 carbidopa, 484 bisphosphonates, 163, 437, 439–42, 680 homeostasis, 139–46 carbohydrate metabolism, 274 blastocyst, 296 homeostasis in pathology, 145, 146 carboline (β), 532–4, 536, 539 bleomycin, 380, 413, 422 intracellular concentration, 140 carboplatin, 416 blood-brain-barrier, 18, 24, 28–9, 60, 263, intracellular pools, 145 carboxylation, 136 346, 454, 483, 484, 494, 504–7, in mitochondria, 143, 435–6 carcinogenicity, 670 513, 521, 527, 541, 543, 569, mitochondrial uniporter, 143–4 cardiac arrhythmias, 35, 45, 78, 87, 320, 590, 592, 594, 700 in muscle function, 144 324, 325, 327–8, 330, 338, 351, bortezomib (PS341, Velcade), 387–9, 417, in the nucleus, 145 493, 678, 681 425–6 oscillations, 144–5 cardiac conduction, 313, 323, 325 bosutinib, 233 pumps, 141–4 cardiac failure, 320, 325, 606, 631, 636 botulinum toxins A, B, 118, 160–161, 329, endoplasmic reticulum, 142–4 cardiac glycosides, 58, 141–2, 347–9, 381, 392, 475, 501, 505 mitochondria, 143 354, 358 Bovet, D., 13 plasmamembranes, 141 cardiac negative chronotropism, 560 Boyle, 11 in trans-Golgi network (TGN), 145 cardiac negative inotropism, 560 brain-derived neurotrophic factor (BDNF), transporters, 141 cardiac positive chronotropism, 558, 560 157, 203, 205, 566 calcium (Ca2+) channels cardiac positive inotropism, 558, 560 brefeldin A, 164, 474 voltage gated (VGCC), 326–31 cardiomyocyte, 301 bretylium, 49, 320, 325 cellular organization, 326–7 carfilzomib (PR-171), 387, 426 bromocriptine, 458, 461, 483, 489, classification, 327 carnitine, 438 490, 494 drug action, 328, 331 carnitine palmitoyl transferase I, 438 Buchheim, R., 12 molecular structure, 327, 329 carteolol, 492 bungarotoxins pharmacology, 327 carvedilol, 263–5, 325, 492–3 α-bungarotoxin, 95, 185–7, 501, 503 calcium-dependent activator protein for caspase recruitment domain (CARD), 409 β-bungarotoxin, 476 secretion (CAPS), 567 caspases, 380, 389–91, 408–9, 549, 564 n-bungarotoxin, 503 calmodulin, 113, 131, 132, 142, 145, 168, inhibitors (IAPs), 411 bunitrolol, 263 340, 455, 581, 598, 604, 630 procaspases, 409 bupivacaine, 325, 337 calpain, 145, 380, 382–4, 387, 390–392 cassette dosing, 702 buprenorphine, 128–9, 574 calpastatin, 145, 380, 382–3, 391–2 catalase, 434

0002534462.indd 717 5/11/2015 2:38:20 PM 718 Index

catecholamine receptors, 487 cell death defective protein (ced), 408 choline acetyltransferase inhibitor, principles of drug action, 490 Ced-3, 408 N-methyl-4-(1-naphtylvinyl) catecholaminergic system, 477 Ced-4, 408 pyridinium, 499 in the CNS, 480 Ced-9, 408 cholinergic system, non-neuronal, 497 catecholaminergic transmission, 477 Egl-1, 408 cholinergic transmission indirect sympathomimetic drugs, 485 cell therapy, 296, 299–303 in CNS: in learning, memory and catecholamines, 65, 177, 189–91, 265, cephalexin, 642 movement, 497–8 359–61, 373, 453, 477–86, 491, cephalosporins, 14, 56, 642, 645 in PNS: cholinergic sympathetic system, 493, 495, 544, 555, 560, 562 cephamycins, 642 496–7 catabolism, 485 cerebral-spinal fluid (CSF), 29 cholinesterases (ChEs), 499–500 release, 484 cetuximab (Erbitux), 214–15, 417, 427–9 inhibitors (ChEIs), 500, 505 reuptake, 485–6 cevimeline, 502, 504, 506 reactivators, 500 synthesis, 483–4 Chain, E., 14 choline transporter 1 (CHT1), 499 vesicular storage, 484 channelopathies, 313–14 chromanol, 337 catechol-O-methyltransferase (COMT), chaperones, 117 chromatin, 426 67, 485–6, 495 chelating agents, 684 chylomicron(s), 446, 448, 450 catenin (β-), 170 chemical antagonism, 685 cimetidine, 15, 49, 57, 65, 71, 108, 527–8, cathepsins, 383–4 chemicals, 675 680, 682 cationic channels, 339 classification and labeling, 675 cinnoxicam, 612 cyclic nucleotide-gated (CNG) channels, documentations, 666 ciprofloxacin, 71, 642, 649 341–3 chemistry cisapride, 71, 338, 518, 682 hyperpolarization-activated cyclic combinatorial, 690 cisplatin, 416, 418 nucleotide-gated (HCN) medicinal, 692–3 citalopram, 71, 263, 366, 369, 370, 515, channels, 341–3 chemokine receptors, 219, 227 517, 682 modulated by cyclic nucleotides, 339–42 Class I hematopoietin receptors, 217 clarithromycin, 71, 338, 642, 682–3 caveolae, 576 Class II hematopoietin receptors, 218 clathrin, 471 CD44, 226 Hematopoietin, 217–18 coated pit, 471 signal transduction, 229, 232–3 The IL-1/IL-18 Receptor Family, 218 coated vesicles, 471 Cdc42, 156 signal transduction, 229 clavam, 642 CD95/CD95R, 410, 411, 413 The TNF Family, 219 clavulanic acid, 642 cefaclor, 642 tyrosine kinase receptors, 218 clearance, 54, 74, 77–8, 84 cefbuperazone, 642 chemokines, 227, 229 creatinine, 57–8, 84–8, 448 cefotaxime, 642 chemoreceptor trigger zone (CTZ), 29, hepatic, 59 cefoxitin, 642 483, 494 organ, 54 ceftazidime, 642 chemotaxis, 560 renal, 57 ceftriaxone, 542, 642 chemotherapy, 5, 641–61 clenbuterol, 492 celecoxib, 71, 611–13, 682–3 chlorambucil, 417–18 clindamycin, 642 celiprolol, 492–3 chloramphenicol, 14, 49, 65, 69, 71, 642, clinical investigation, 708–10 cell cycle, 405–7 647–8, 685 ethical principles, 708 Cdc 25 phosphatase, 405, 406 chlordiazepoxide, 14, 539 phases, 709–10 Cdk-activating kinase (CAK), 405, 406 chloride (Cl-) channels, 532–40 regulations, 708 CDK inhibitor (CKI), 407 chloromethylhistidine (α-), 525 clinical protocols, 709 checkpoints, 407 chlorpheniramine, 527 controls, 711 cyclin B, 406 chlorpromazine, 14, 49, 62, 69, 71, 338, design, 710–711 cyclin-dependent kinase (CDK), 405 494, 517 end points, 711 cyclins, 405 chocolate, 123, 562 fast track, 712 E2F1, 406 cholecystokinin (CCK), 482, 497, 524, non inferiority, 711 G0, 405 565, 567, 570 primary hypothesis, 711 G1, 405 cholera toxin, 193–4 proof of concept, 712 M, 405 cholesterol, 15, 50, 62–4, 117, 163, 273, randomized, 711 PEST sequence, 405 283, 288–91, 328, 345, 393, sample size calculation, 711–12 Retinoblastoma binding protein (pRb), 439–51, 535–6, 559–60, 603, sub group evaluation, 712 406, 409 614, 618, 633, 649, 689 validity, 711 S phase, 405 biosynthesis, 439–41 clobenpropit, 527–8 cell death, 407 oligonucleotide conjugation with, 286–7 clofibrate, 282, 440 apoptosis, 407, 558 cholesterylester transfer protein (CEPT), 449 clomipramine, 71, 517–18 necroptosis, 413 inhibitors, 449–50 clonazepam, 539 necrosis, 407, 412, 558, 562 choline, 475, 497–9, 502, 504 clonidine, 49, 78, 481, 487, 491–2 programmed cell death, 407 choline acetyltransferase (ChAT), 498 clopidogrel, 71, 261–3, 560–561, 711

0002534462.indd 718 5/11/2015 2:38:21 PM Index 719

clostridial toxin, 329, 475 cycloserine, 642, 644–5 death receptors, 111, 115, 408 clozapine, 15, 65, 71, 264, 490, 494, cyclosporin A (CsA), 15, 49, 71, 222, 253, deltorphin, 574, 576 516–18, 682 263, 353, 413, 436, 626–7, dementia, 86, 385, 483, 498, 504, 549, c-myc, 408, 637 629–30, 679–80, 682–3, 685 550, 592 CNS depressants, 124 clinical use, 631 denufosol, 560–561 co-activators, 245, 246–50, 254 pharmacokinetics, 631 deoxyribo nucleic acid (DNA) coagulation factors, 116 cylexin (CY-1503), 233 polymorphisms, 266 cocaine, 12, 38, 123–4, 126, 321, 324, 338, cyproterone acetate, 281 topoisomerase inhibitors, 421–3 346, 361, 364, 366–8, 371–2, cysteine proteases, 380 dependence, 121–9 374, 482–3, 486–7, 495, 512, cystic fibrosis, 136, 303, 306, 311, 314, clinical phenomena, 125 539, 544, 567, 584 345–6, 387, 559–61, 600 diagnostic criteria, 125 codeine, 49, 57, 62, 260–261, 526, 573, cystine-glutamate exchanger, 544 physical, 580, 582, 584 679, 684 cytarabine, 420 psychic, 7, 122–9, 583, 584 coffee, 12, 562 cytisine, 502–4 symptoms, 125 cola, 562 cytochrome c, 335, 384, 389–90, 409–11, therapy, 128 colchicine, 94, 420, 474, 653 434–7, 596, 599–601, 605, 607 deprenyl, 525–6 colistin, 642–3, 650 cytochromes p450 (CYPs), 62–5, 258–62 derived no effect level (DNEL), 674 collagen, 42, 149, 205, 228, 300, 395, 399, catalytic cycle, 63 dermorphin, 574, 576 437, 597, 618 cellular localization, 63 desipramine, 35, 71, 338, 372 compound 48/80, 525 distribution, 68 desogestrel, 280 computer-aided drug design (CADD), 692 drug interaction, 682 dexamethasone, 49, 70, 187, 275, 280, concanavalin A, 525 drug metabolism, 681 613, 630 connexons, 465–6 enzymes, 62–5 dextran, 46, 525–6 conotoxin (α-), 502 evolution, 64 dextromethorphan, 573 constitutive androstane receptor, 272–83 families, 64 dextropropoxyphene, 574 drug metabolism, 283 isoforms, 71 diabetes insipidus, 192 contraception, 280 polymorphism, 67, 258–62 diabetes mellitus, 14, 117, 150, 152, 170, Contract Research Organization toxicity, 62, 72 192, 202, 248, 282, 295, 298, (CRO), 709 cytokine receptor, 217–24, 235 314, 320, 332–5, 391, 438, 440, convertases, 386 agonistic effect, 238 443, 446–7, 452–61, 695 endothelin convertase, 386 antagonistic effect, 237 diacylglycerol (DAG), 194, 196, 197 copy number variation (CNV), 257 soluble, 235 diacylglycerol acyltransferase, 445 co-regulators, 247–50 soluble viral, 236 inhibitors, 446 co-repressors, 246–50 cytokines, 114, 220–224, 236–8, 637–8 pharmacological/clinical activity, 446 CoREST, 249 adaptive immunity, 222–3 diadenosine polyphosphates (APxA), corneal lesions, 559 anti-inflammatory, 223 559–60 corticotrophin releasing factor (CRF), classification, 217 diamine oxidase (DAO), 521 569, 570 hematopoietic, 220 diazepam, 14, 49, 57, 61–2, 83, 534–5, receptors, 569, 570 innate immunity, 220–222 539, 582 cortisol, 64, 273, 280, 452–3 pharmacology, 223–4 diazoxide, 320, 335, 437, 459 cortisone, 14, 61, 280 cytosine arabinoside (Ara-C), 419–20 diclofenac, 71, 335, 611–13, 682, 710 cotransmission, 567, 569 cytoskeletal matrix, 117 diffusion, 23–6 crizotinib (Xalkori), 214 cytoskeleton, 112, 117, 156, 159, 170, 198, facilitated diffusion, 26 cromakalim, 320, 335 210, 227, 387, 473, 605 simple diffusion, 24–5 crosstalk, 168 cytosolic 5’ nucleotidase, 555 through membrane channels, 26 curare, 14, 501, 503–4, 506, 508 digoxin, 32, 34, 57, 77, 79, 86, 93, 263, cyanoguanidines, 335 dacarbazine, 416–17 347–9, 680–681, 683–6 cyclic polypeptides, 642 daclizumab, 239, 628, 636, 695 dihydropyridines, 320–321, 326, 328, 330 cyclizine, 527 dalcetrapib, 449–50 diisopropyl fluorophosphate (DFP), cyclooxygenase (COX), 461, 610–613 danazol, 281 380, 500 COX-1, 610–613 danger signals, 553 dilazep, 556 COX-2, 610–613 dantrolene, 321 diltiazem, 35, 49, 71, 263, 321, 325, 327, gene, 610 dapsone, 642 330, 341, 343, 682–3 inhibition, 611–13 daptomycin, 642–3, 650 dimaprit, 527–8 protein, 610–611 dasatinib, 233, 424 dimethindene, 527 cyclophilin A (CypA), 436 daunorubicin, 413, 416, 422–3 dipeptidyl peptidase-4 (DPP-4), 455 cyclophilin D (CypD), 436 d-curarine, 525 inhibitors, 459–60 cyclophosphamide, 417, 626–30, 635 death domain (DD), 410, 411 diphenhydramine, 338, 506–7, 527 cyclopyrrolones, 534, 539 death effector domain, (DED), 409, 411 diphenoxylate, 573

0002534462.indd 719 5/11/2015 2:38:21 PM 720 Index

dipivefrine, 492 doxorubicin, 42–3, 263, 413, 416, 422–3 site, 68–9 dipyridamole, 556, 561 doxycycline, 642 therapeutic relevance, 72 diquafosol, 559, 561 droperidol, 338, 494 names, 4 discovery droxicam, 612 orphan, 698 alkaloid, 12 drug, 4, 93 potency, 7

benzodiazepine, 14 acidity constant (pKA), 24 research (R), 691–2 glucosides, 12 affinity, 6. 7 selectivity, 7 penicillin, 14 agonist, 6 target, 93 vaccines, 13 allosteric, 6 tolerance, 118 disopyramide, 325, 338 agonist inverse, 6, 109 drug metabolism and pharmacokinetics dissociation constant, 96 agonist partial, 6 (DMPK), 700–707 distribution, 21, 45, 46–53 antagonist, 6 in vitro, 700–707 redistribution, 83 biological, 5, 16, 694 in vivo, 700–707 volume, 46, 48–9, 74, 81, 84 biosimilar, 5 drug response, genetic variability, 256–7 disulfide bonds, 136 competition, 6, 99 drugs approved per year, 709 disulfiram, 128–9, 682 concentration(s), 5, 27, 46, 48, 50, 59, drugs of abuse, 124 diuretics, 8, 15, 56, 100. 101, 280, 78–9, 86, 418 entactogens, 124 320–321, 347, 356, 357, 461, dependence (see dependence) hallucinogens, 124 679–80, 685–6 development, 689–99, 700–713 psychostimulants, 124, 486–7 dobutamine, 331, 492 clinical, 708–13 sedative hypnotics, 124 dofetilide, 325, 337–8 diagnostic tests, 713 dry eye syndrome, 561, 563 dolasetron, 516–17 failure rate, 709, 712 dynorphin, 567, 570, 572, 574–6, 578, Domagk, G., 13 process, 15, 16 582, 584 domoic acid, 549 discovery, 700–703 dyslipidemia, 282, 439–51, 591 donepezil, 500, 505 generic, 4, 5, 612, 691–2, 694, 706 dopamine, 125–7, 190, 492, 512, 514–15, herbal, 5 echinocandins, 651 518, 582–3 industries, 12, 13, 17 ecothiopate, 500 dopaminergic receptors, 488 interactions, 611, 678–86, 705–6 ecstasy (MDMA), 124, 126, 361, 366, agonists in cardiogenic shock, 493 dietary supplements/components, 485, 515 agonists in disorders of the CNS, 494 685 ectonucleotidases, 555–6 dopaminergic agonist, 461 grapefruit juice, 683 ecto-ADPase, 555 dopaminergic antagonist, 494 herbal medicine, 685 ecto-ATPase, 555

D2 receptor, 190, 192, 195, 198 pharmacodynamic, 684 edrophonium, 499–500, 505 drugs, 493–4 pharmacokinetic during efalizumab (Raptiva), 233, 628, 636 dopaminergic system, 481–3 absorption, 679 efavirenz, 655, 660 distribution, 481 pharmacokinetic during efficacy, 100, 103, 108 dopamine and behavioral disorders, 482 biotransformation, 681 theory, 104 dopamine on the ctz, hypothalamus and pharmacokinetic during EGFR see growth factor receptors pituitary, 483 distribution, 681 eicosanoids, 190, 608–20 dopaminergic nigrostriatal system and pharmacokinetic during excretion, 683 epoxyeicosatrienoic acids, 608, movement control, 482 metabolism, 24, 59, 61–72, 258, 283, 615–17 functions in the CNS, 482 673, 678, 681–2, 700–707 hydroxyeicosatetraenoic acids, 608, dopamine transporter (DAT), 126, conjugation, 34, 58, 62, 66–8, 258, 615–17 360–361, 370–371 634, 703–4 isoeicosanoids, 608, 617–18 pharmacology, 371 extrahepatic methabolism, 68 isoprostanes, 608, 617–18 dose, 74 genetic polimorphisms, 258 leukotrienes, 608, 615–16, 620 absorbed, 74–5, 78 inducers, 70 prostanoids, 608, 610–614 age, 84–7 induction, 59, 65, 69–70, 679, receptors, 618–19 attack dose, 80 681–5, 695 eletriptan, 517 dosage corrections, 84–7 inhibition, 71–2 elimination, 22, 53 dosing interval, 79 inhibitors, 71 rate constant, 40, 53 hepatic pathology, 86 intestinal flora, 69 time constant, 74 loading dose, 80 phase I, 62 elongation factors, 646 maximal tolerated dose (MTD), 669–70 phase II, 62, 66 empathogens, 124 multiple, 77–8 phase II enzymes, 262–3 enalapril, 387, 567 renal pathology, 86–7 phase II enzymes-polymorphisms, encainide, 325 dose-response curves, 99–102 262–3 endo-adenosine deaminase, 555 doxazosin, 492 phase II enzymes-polymorphisms- endocannabinoids (ECs), 586–95 doxepin, 338, 527 clinical effects, 264 transporter, 288

0002534462.indd 720 5/11/2015 2:38:21 PM Index 721

endocannabinoid system (ECS), 585–95 estradiol, 71, 167, 277–80, 681 farnesyltransferase, 157 anxiety and depression, 591 estrogen receptors, 272–80 Fas-associated protein with death domain biological function, 588–93 agonists, 280 (FADD), 410–411 cancer, 592 antagonists, 280 Fas/FasL, 13, 410, 411 eating disorders, 590 indication, 281 fatty acid immune system, 592 selective estrogen receptor modulators biosynthesis, 440, 443–4 neurodegenerative diseases, 592 (SERMs), 281 desaturases inhibitors, 444 pain and inflammation, 591 estrogens, 42, 58, 264, 271, 272, 277, 280, synthase inhibitors, 443–4 synaptic plasticity, 589 446, 498, 523, 672, 679 pharmacological activity, 444 endocytosis, 23, 25–6, 116, 161, 198, 232, estrone, 280 feed-back loops, 170 360, 383, 439, 456, 471, 475, etanercept, 627, 636, 695 felodipine, 327, 330 582, 654 etaracizumab (Abegrin), 233 fenamates, 335, 612 endomorphins, 574–6 ethacrynic acid, 56, 347, 357, 617 fenfluramine (feh), 366, 370, 513 endonuclease G, 411 ethanol, 62, 64–5, 69–70, 100, 123–4, 126, fenofibrate, 71, 440 endoplasmic reticulum (ER), 62, 63, 65, 128, 350, 533–4, 537, 539–40, fenoldopam, 104, 490 66, 117, 135, 139, 142, 157, 339, 631, 682 fenoprofen, 612 346, 352, 353, 380, 382, 383, ethanolamine, 530, 587 fenoterol, 492 385, 409, 426, 442, 450, 484, ethics committee, 709 fentanyl, 573, 582 535, 538, 566, 568, 571, 610 ethinyl estradiol, 280, 681 fexofenadine, 263, 527

endoprotease, 396 ethosuximide, 320, 327, 331 F0F1 ATP synthase, 436 endorphins, 94, 567, 572 ethylenediamine, 527 fibrates, 70, 282, 438, 440, 447, 679, 684 β-endorphins, 567 ethylephrine, 492 pharmacological activity, 447 endosomes, 25, 115, 145, 161, 199, 290, etodolac, 612 fibrinogen, 228–9, 233 360–361, 372, 381, 471 etofibrate, 440 fibronectin, 115, 205, 217–18, 228–9, 233, endothelin, 158, 381, 386–7 etoposide, 416, 422–3 395–400 enhancer, 246 etoricoxib, 611–13 Fick’s law, 24 enkephalins, 29, 94, 501, 510, 562, 565, etretinate, 282 first-pass effect, 35, 58 570, 572, 574–5, 578 European Chemical Agency (ECHA), 675 FK-506, 71, 222, 253, 263, 338, 627, entactogens, 124 European Food and Safety Authority 630–633, 679–80, 682 entecavir, 659 (EFSA), 675 flavin monooxygenases (FMO), 62–3 enteramine, 509 European Medicines Agency (EMA), 691, flecainide, 71, 325 enterochromaffin-like cells (ECL), 521 708 Fleming, 14 entero-hepatic cycle, 58 excipient, 4, 32, 36, 73 fluconazole, 71, 682 enzymes generating lipid second excitotoxicity, 146, 547–9 flucytosine, 651, 654 messenger, 210–211 excretion, 55–9 fludarabine, 419 ephedrine, 485, 492 hepatic, 58 flufenamic acid, 612–13 epibatidine, 502, 504 renal, 55–8 fluoromethylhistidine (α-FMH), 521, 523, epigenetic modulators, 426 exocytosis, 23, 140, 168, 360, 411, 439, 454, 525–6 demethylating agents, 426 455, 467, 470–471, 475, 514, 568 fluoro-oxindoles, 335 HDAC inhibitors, 426 exon skipping, 286–7 fluorouracil (5-FU), 35, 262, 419–20, 653 non-coding RNA, 426 extracellular matrix, 46, 114, 211, 225, fluoxetine, 71, 366, 370, 486, 514–15, 517 epipodophyllotoxins, 416, 423 228, 384, 395, 466 fluoxymesterone, 281 epirubicin, 416, 422–3 extracellular protease, 395 flupirtine, 320, 335, 339 epoxide hydrolases (EH), 62, 64 antagonists, 399 flurbiprofen, 611–13 epoxomicin, 426 inhibitors, 399 flutamide, 281 equilibrium, 95–6 extraction index, 54–5 fluvastatin, 71, 440 conditions, 96 fluvoxamine, 71, 514–15, 517, 682 constants, 95 factor(s) flux-to-volume ratio, 27, 52 ERK, 147–8, 413, 581, 583 general transcription (GTF), 243 folic acid, 58, 288, 418–19, 541, 629, cascade, 151–2 inducible, 251–2 642, 649 ERK5, 150 transcription, 243–6, 251–2 follicle-stimulating hormone (FSH), 42,

Erlich, 13 FADH2, 435 190–191, 481 erlotinib (Tarceva), 152, 212, 214–15, 416, FAK, 230 fomivirsen, 654 424, 426 famciclovir, 654 Food and Drug Administration (FDA), erythroidine (β-), 502–3 famotidine, 527–8 128, 132, 138, 152, 214, 256, erythromycin, 14, 34, 71–2, 263, 338, 642, fampridine, 505 263, 299, 303, 388, 443, 451, 647, 679, 682–5 farnesoid X receptor, 272–82 590, 592, 656, 658, 672, 691, escitalopram, 515, 517 farnesyl pyrophosphate synthase inhibitors, 696–7, 704, 706, 708–9 esmolol, 325, 492 441–2 formoterol, 492

0002534462.indd 721 5/11/2015 2:38:21 PM 722 Index

foscarnet, 656 glial cells, 28, 202, 324, 362, 368, 466, pharmacology, 363 frovatriptan, 517 471, 472, 530, 535, 541, 543, 603 substrates, 364 furin, 386–7, 393 gliflozins, 458 glutaminase. 542 furosemide, 49, 56–7, 101, 347, glinides, 332–3, 455, 458–9 glutathione coniugation, 68 357–9, 532 glomerular filtration, 82, 84–5, 446, 479, glutathione peroxidase, 434 fusidanes, 642 557, 603, 609, 632 glycemic control, 452–61 fusidic acid, 642, 648 glucagon, 106, 190, 343, 452–4, mechanisms, 452–7 458–60, 563 pharmacology, 457–61 GABA see γ-aminobutyric acid (GABA) glucagon-like peptide-1 (GLP-1), 351, glycine receptors, 111, 175 GABA-α-ketoglutarate transaminase, 530 454, 458–60 glycopeptides, 642, 645, 648 GABAergic transmission, 529–40 glucocorticoid receptor, 269–278 glycosylation, 135, 138 gabazine, 531, 533 agonists, 278 inhibitors, 138 galantamine, 500, 505 regulated genes, 278 glycosylphosphatidylinositols, 137 Galen, 8, 9 selective agonists, 278 Golgi apparatus, 117, 135, 143, 156, 157, Galileo Galilei, 11 glucocorticoids, 110, 221–3, 269, 278, 163, 380, 383, 385, 566, 599 γ-aminobutyric acid (GABA), 190, 470, 370, 609, 618, 632, 679, Good Clinical Practices (GCP), 696, 708–9 512, 529–31 684, 6268 Good Laboratory Practices (GLP), 672, 696 distribution, 529 mechanism of action, 632 Good Manufacturing Practices (GMP), 697 metabolism, 530 resistance, 280 G-protein-coupled receptor kinase (GRK), receptor undesired effects, 276 192, 194

GABAA, 531–5 glucose, 157, 162, 167, 169, 231, 280, 282, G-protein-coupled receptors (GPCRs),

GABAA extrasynaptic, 533–4, 321, 332–4, 350, 438, 440, 189–201, 521, 555, 557, 559, 537, 539 446–8, 452–61, 467, 478, 480, 565, 568

GABAA subtypes, 532–4 491, 493, 497, 499, 513, 541, dimerization, 192

GABAB, 190, 192, 537–9 551, 559–60, 563, 586, 599, 605, effectors pathways, 195–8 release, 530–531 634, 652 GPR17, 559 reuptake, 530 control, 452 G-protein-independent signaling, synthesis, 530 intestinal absorption, 460 199–200 transporters, 367 modulation of GLUT4 activity, 456 interacting proteins, 198–200 pharmacology, 369 phosphorylation, 454 AKAP, 198 structure, 368 transport, 452 β-arrestin, 192, 199–200 ganaxolone, 536 transporters (GLUT), 453–4 Homer, 198 ganciclovir, 655–6 uptake, 452 NHERF1, 200 ganglioplegic, 504, 506 glucosidase (α-), 460 RAMP, 199 gap junctions see junctions glucosides, discovery, 12 RGS, 198 GAPs, 158, 164 glucuronidation, 66 ligand binding site, 191 gastric parietal cell, 350 glutamate (glutamic acid), 190–191, 470, mutations, 192 gastric secretion, 350 512, 541–52 polymorphisms, 192 G-coupled cholecystokinin-B receptor metabolism, 541–2 structural organization, 190–192 (CCKB/gastrin receptor), 524 synapses, 543–5 G proteins, 192–5 GDIs, 159 synthesis, 541–3 activation/inactivation cycle, 193 gefitinib (Iressa), 214–15, 416, 424 transport, 542–4 βγ complex, 193–7 gemcitabine, 416, 419–20 glutamate decarboxylase (GAD), 529–30, effectors, 194–5 gemfibrozil, 71, 282, 440, 447, 682 539–40, 542 regulators of G protein signaling gemtuzumab, 239, 695 glutamate dehydrogenase, 542 (RGSs), 193 gene delivery, 305 glutamate receptors, 544–9 α-subunits, 193–7 generic(s) see drug ionotropic, 545–6 modification by toxins, 194 gene therapy, 43, 262, 284, 295, 303–6, AMPA receptors, 469, 544–6, mutations, 194 303–6 550, 604 Graft Versus Host Disease (GVHD), ex-vivo, 304 kainate receptors, 43, 545–6 626–7, 629, 631 in-vivo, 304 NMDA receptors, 117, 129, 141, 469, granisetron, 338, 516–17 genetic polymorphisms, 258 545–7, 549–50, 604 granulocyte colony-stimulating factor clinical effects, 258 ionotropic agonists, NMDA, 523 (G-CSF, filgrastim), 218, drug pharmacokinetics, 258 metabotropic agonist, ACPD, 548 220–221, 637–9, 694–5 genomics, 694 metabotropic receptors (mGluRs), 190, granulocyte-macrophage colony- gentamicin, 57, 642, 647, 685 192, 198, 546–7 stimulating factor (GM-CSF), gepirone, 516–18 glutamate transporters (EAAT), 361–2 217–8, 220–221, 237, 634, geranylgeranyltransferase, 157 distribution, 352 637–9, 694 gimatecan (ST1481), 421–3 function, 352 grapefruit juice, 682–3, 686

0002534462.indd 722 5/11/2015 2:38:21 PM Index 723

grepafloxacin, 338 H4R, 520–526 imipenem, 642, 685

growth factors, 203 H2R agonists, 528 imipramine, 49, 57, 61, 71, 369–70, 486,

epidermal (EGF), 26, 113, 116, 151, H4R agonists, 527, 528 515, 682

154–5, 168, 202–3, 205, 207, H4R antagonists, 527, 528 immepip, 527–8

218, 236, 275, 397, 428, 610, 637 H2R selective antagonists, 527, 528 immune cells, 558, 564 nerve growth factor (NGF), 113, 151, histaminergic neurons, 523 immune system, pharmacological 167–8, 171, 202–3, 205–6, 498 histaminergic transmission, 520–528 modulation 625 receptors, 202–16 histidine-decarboxylase (HDC), 520 immunoadiuvants, 639 activation and signal transduction, histone acetyltransferase (HAT), 248 immunomodulators, 114, 630, 636, 638, 657 205–13 histone code, 249 immunostimulant drugs, 625, 637–9 epidermal growth factor receptor histone deacetylase (HDAC), 248–9 immunosuppressive drugs, 187, 222, 224, (EGFR), 203–5, 207, 214–15, histones, 135, 148, 248, 274, 418, 425 296, 338, 625–37 424, 427–8, 661, 691 HIV, 392 implitapide, 450 functional domains, 204–5 H+/K+ ATPase, 349–51, 523 impromidine, 527–8 molecular structure, 204–5 gastric pump, 350 incretin effect, 454–5 target for anticancer drugs, 215 inhibitors, 347, 351 incretins, 458–60 vascular endothelial growth factor pharmacology, 350 indacaterol, 492 (VEGF), 150, 203, 207, 214–15, structure, 350 indinavir, 71, 263, 387, 393, 682–3, 685 254, 417, 428–9, 571 HMG-CoA reductase inhibitors see statins indobufen, 612 GSKβ3, 169, 170 homatropine, 506–7 indomethacin, 57, 71, 612 guanabenz, 492 hormone replacement therapy, 278 inflammation, 511 guanfacine, 492 hormones, 190, 191 infliximab, 239, 627, 636 guanine nucleotide exchange factors Human Genome Project, 691, 694 inosine, 555, 629 (GEFs), 158, 163 Huntington’s chorea, 562 inositoltrisphosphate (IP3), 194, 196, 198 guanylyl cyclases, 604, 607 hydralazine, 34, 262 receptor, 143–4 hydrocortisone, 38, 62, 187, 634–5 insulin, 16, 25, 31, 36, 42, 113, 117, 136,

half-life (t1/2), 38, 40, 53–4, 75, 77 hydrogen peroxide, 433 150, 157, 170, 203–6, 275, 282, hallucinogens, 124 hydrolysis, 65 320–321, 327, 331–3, 335, 389, halofantrine, 338 hydromorphone, 573 393, 444–5, 447–8, 454–61, 493, haloperidol, 71, 108, 337–8, 494, 517 hydroxitriptamine see serotonin 557, 559, 563, 566, 591, 600, halothane, 62, 65, 321, 540, 682 hydroxybutyric acid (γ-) (GHB), 539 603, 684–5, 685 Harvey, 11 hydroxyindolacetaldehyde, 513–14 exocytosis, 454 hazard identification, 666, 669, 673 hydroxyindoleacetic acid (5-HIAA), IR tyrosine kinase, 457 heart failure, 117, 251, 264, 269, 282, 342, 511, 514 modulation of signaling, 459–60 347–9, 492–3, 560, 602, 678 hydroxylation, 135 receptor (IR), 454–5 heart preconditioning, 560 hydroxyl radical, 433 resistance, 461 heart rate, 196, 320, 342, 354, 479, 489, hydroxytryptophan (5-OH-tryptophan), 513 secretion, 455 491, 493, 507, 561, 579 hydroxyzine, 338 integrase inibitors, 655, 660 hemicholinium (HC3), 499 hyperlipidemia, 444, 447, 459, 632 integration of receptor signaling, 166–71 heparin, 42, 49, 203, 228, 290, 521, 525, 585 hypertension, 561 integrins, 114, 226–8 hepatitis c, 429, 657 hypnotics, 56, 124 activation, 229 heroin, 61, 124, 483 hypoglycemia, 453 ligands, 290 hexamethonium, 57, 112 endocrine response, 453 signal transduction, 229–32 hexokinase, 437, 454 hypoglycemic drugs, 332, 458 FAK, 230 high production volume (HPV), 675 hypothalamic–pituitary–adrenal (HPA) Src, 230 high-temperature requirement A axis, 513 interactions (HTRA), 388 hypoxia, 553–4, 562 drug–diet, 686 high throughput screening (HTS), 690 drug–drug, 63, 108, 641, 678–86 Hippocrates, 8 ibuprofen, 71, 612–3 pharmacodynamics, 684 histamine (2-(imidazol-4-yl)ethylamine), ibutilide, 325 pharmcokinetics, 678 28, 190, 520 ICAM-1, 636 interferons (IFNs), 114, 218, 236, 637–8, [3H]-histamine, 526, 527 idarubicin, 416, 422–3 657, 694–5 histamine-N-methyltransferase, 521 If current, 196 interferon α (IFNα), 17, 218, 236–7, histamine receptors imatinib mesylate (Gleevec), 212, 214, 629, 638–9 antagonists (antihistamines), 14, 263, 233, 263, 416, 423–4 interferon β (IFNβ), 17, 42, 71, 114, 338, 483, 520, 527, 680, 684 imetit, 527, 528 236–7, 280, 599, 637, 638,

H1R, 521 imidazole-N-methyltransferase, 525 657, 694–5

H2R, 520 imidazopyrazines, 335 interferon γ (IFNγ), 218, 222–4, 236,

H3R, 521 imidazopyridine, 532–5, 539 597, 599, 605, 627, 630, 638–9

0002534462.indd 723 5/11/2015 2:38:21 PM 724 Index

interleukins, 5, 114, 217, 389, 637, 639 isosorbide, 597, 606 LTC 4, 615

IL-1, 236–7, 290, 380, 409, 599, isotretinoin, 282 LTD 4, 615 609, 637 ivabradine, 196, 321, 341–3 leukotrienes receptors, 620 IL-2, 17, 115, 243, 637, 694 ivermectin, 353 levcromakalim, 335 IL-3, 114, 217, 638 levobunolol, 492 IL-5, 217 JAK2 tyrosine kinase, 200 levofloxacin, 263, 338, 642 IL-6, 115, 217, 220–223, 237–9, 290, JNJ7777120, 526–7 levorphanol, 573 560, 627–8, 636 JNK, 147–8, 152–3, 413 lidocaine, 35, 320, 325 IL-7, 217–20, 237, 637 josamycin, 642 lifetime, 40 IL-10, 114 junctional epidermiolysis bullosa (JEB), 306 ligand binding domain, 179, 272, 544–5 IL-18, 237 junctions lincomycin, 642–3 IL-22, 114 adherent, 56–7, 226, 232 lincosamids, 642, 648 intestinal natriuretic peptide, 114 desmosomes, 232 linezolid, 642, 648, 650 intetumumab (CNTO-95), 233 gap, 465–6 linopirdine, 320, 337 intracellular receptors, 6, 110 neuromuscular, 111, 116–17, 176, 180, lipid activating functions, 274–7 328, 475, 497, 501–2, 508 conjugation, 133, 288, 290 classification, 268, 272 thigh, 32, 232 lowering drugs, 439–51 DNA binding, 272, 274 metabolism drugs and indications, 271, 278–83 kanamycin, 49, 642, 647 transcriptional control genes, 446 hormone responive element (HRE), 269 kernicterus, 51 modifications, 136 ligand binding domain, 272 ketamine, 43, 124, 126, 549–50 rafts, 117 ligand binding pocket, 272 ketanserin, 338, 491, 516–17 transfer proteins, 448 ligands, 274–7 ketoconazole, 71, 263, 280, 338 lipofectin, 287 nomenclature, 272 ketoprofen, 612 lipooxygenase, 608–9, 615–17 regulation of gene expression, 272–7 ketorolac, 612 inhibitors, 616 specificity of action, 278 kidney, 55–8 5-lipooxygenase, 609, 615–16 intrifiban (Integrilin, eptifibatide), 233 kinetic constants, 96 12-lipooxygenase, 609, 616 intrinsic activity, 104 kinetics 15-lipooxygenase, 609, 616 inulin, 56, 85 first-order, 25, 38–41, 74 pathway, 615 iodofenpropit, 526–7 multicompartmental, 81–82 lipopeptides, 642 iodoprossifan, 526 zero-order, 38 liposomes, 43, 287 iodoxuridine, 656 kiss and run, 471 lithium, 14, 34, 57, 197–9, 338, 680, 684 ion channels, 175–88, 311–59, 468 kurtoxin, 327 liver, 58–9 anionic channels, 339 liver X receptors, 446–8 cationic channels, 339 labetalol, 35, 492 regulated genes, 446–8 classification, 312 lactacystin, 387, 426 synthetic ligands, 446–7 function, 312 lactams (β-), 642, 645 lomitapide, 450 gating mechanisms, 312 laminin, 228 long-term potentiation (LTP), 558, 561 current-voltage relationship, 315 l-amino acid decarboxylase (AADC), 524 loop diuretics, 347 ligand-gated, 111, 113, 175–88, 312, lamivudine, 655, 659 loperamide, 263, 573 501, 568 lamotrigine, 320, 325 lopinavir, 387 rectification process, 315 Langmuir isotherm, 97 loratadine, 527 structure, 316 lapaquistat, 440, 443 lovastatin, 440 voltage-dependent anionic channels lapatinib, 214–15 l-tryptophan, 513–14, 518 (VDAC), 411, 436 latrotoxin (α-), 475–6 lumiracoxib, 611–13, 710 ionophores (A23187, X527A), 525 Lavoisier, 11 luteinizing hormone (LH), 25, 126, ipilimumab, 239 law of mass action, 99 190–192, 481, 489 ipratropium, 506 l-DOPA, 29, 34, 494, 681, 683 receptor, 190–192, 195 ipsapirone, 514, 516–17 lead compound, 692 lysergic acid (LSD), 124, 512, 516–17 iPS cells, 298 lead optimization, 701–3 lysophosphatidic acid, 190 irinotecan (SN38), 262–3, 266, 416, lectins, 525 lysosomal proteases, 382 421–2, 429 lenalidomide, 627, 630 lysosomes, 117, 135, 198, 290, 361, 372, UGT1A1 polymorphisms, 263 Leroux, 12 380, 382–3 ischemia, 555, 560, 562 leukocytes, 225, 227–9, 231 isepamycin, 642, 647 recruitment, 225, 227, 233 macrolides, 338, 642, 647 isoflurane, 321, 336, 537, 540 leukotrienes, 608, 615–17, 620 macrophages, 558

isoniazid, 146, 262, 530, 682 LTA 4, 615, 616 Magendie, 12 isoprenaline, 57, 338 metabolism, 616 magic mushrooms, 124

isoproterenol, 34–5, 57, 265, 487, 491–3 LTB 4, 615 Malpighi, 11

0002534462.indd 724 5/11/2015 2:38:21 PM Index 725

mapirocin, 642, 648 methylxanthine, 341, 343, 553, 562–3 monoamines transporters, 364–7, 371–2 maprotiline, 366 methysergide, 517 antidepressants, 372 margin of exposure, 668, 675 metilfenidate, 366 distribution, 366 mastocytes, 558 metipranolol, 492 function, 372 MDR1/MDR2, 263, 283, 346 metoclopramide, 34, 483, 494, 517, 680 pharmacology, 366 mecamylamine, 501, 504, 506 metoprolol, 34–5, 49, 108, 325, 492 structure, 372 meclizine, 527 metrifonate, 500 substrates, 366 meclofen, 335 metronidazole, 643 monobactams, 642 meclofenamate, 335, 612 mevalonate pathway, 437. 441 moricizine, 325 mediator, 246 mexiletine, 320, 325 morphine, 57, 124, 126, 573 medroxyprogesterone acetate, 280 mianserin, 527–9 morpholines, 654 mefenamic acid, 612–13 Michaelis–Menten equation, 97 mosapride, 518 MEK, 152 microglial cells, 558 moxifloxacin, 642 melanocyte-stimulating hormones (MSH), microRNA (miRNA), 285 mTOR, 169, 170 567–9 microsomal triglyceride transfer protein mucins, 225–8 melatonin, 511, 513–14 (MPT), 450 multidrug resistant associated proteins, meloxicam, 612 inhibitors, 450–459 26, 658 melphalan, 417–18 microtubule(s), 232, 413, 416, 420, 652 multiple sclerosis, 233, 280, 302, 320, 336, memantine 43, 549–50 acting drugs, 420 505, 521, 539, 553, 590–599, membrane permeability, 701 taxanes, 420 627, 635–7, 638 membrane transporters, 345–58 vinca alkaloids, 420 mupirocin, 642, 648 clinical use, 347 midodrine, 492 muromonab-CD3, 627, 635, 695 memory, 122, 127 mifebradil, 320, 325, 338 muscarine, 501, 504, 507 menopause, 279 mifepristone, 280 muscarinic toxins (MT), 503, 504 meperidine, 65, 573 mineralcorticoid receptor, 272 muscimol, 531, 537 mepyramine, 526–7 antagonists, 280 muscular dystrophy, 295, 387, 563 mercaptopurine, 262, 416, 419 mineralcorticoids, 110, 272, 280 Becker muscular dystrophy (BMD), 301 meropenem, 642 minocycline, 642 Duchenne muscular dystrophy (DMD), mesangioblast, 299 minoxidil, 320, 335 286, 301, 600, 602, 605–6 mescaline, 124 miokamycin, 642 myasthenia gravis, 117, 500, 505, 626–7 mesocorticolimbic system, 125–7, 583 mirabegron, 488, 492 mycophenolate mofetil, 627, 629, 679 meta-analysis, 7 miravirse, 658 myocardial infarction, 437 metabolites mirtazapine, 486, 517 myristoylation, 136 metabolites in safety testing misoprostol, 615, 619 (MIST), 704 mitochondria, 143, 413, 433–8 nabumetone, 612 reactive, 704 permeability transition pores (PTPs), Na+/Ca2+ exchanger (NCX), 346, 353–6, metalloprotease, 381, 399–401 411, 435–7 353–6 cancer, 398 reactive oxygen species (ROS), 411, pharmacology, 354 cancer cell migration, 399 433–8 properties, 354 cell migration, 398 mitochondrial drugs, 437–8 structure /distribution, 353 matrix metallo protease (MMP), 396, 400 antineoplastic agents, 437 N-acetyltransferases (NAT), 67 membrane metallo protease antioxidant, 437 NADH(H+), 435 inhibitors, 399 mitochondrial dysfunction, 437 Na+/H+ exchanger (NHE), 346, 355–6 metastasis, 397, 399 mitochondrial metabolism, 437–8 pharmacology, 356 tissue inhibitors of metalloproteases mitochondrial membrane potential (MMP), structure, 355 (TIMP), 398 411, 433, 437 Na+/H+ exchanger regulatory factor 1 tissue remodeling, 396, 399 mitochondrial translocator protein, 437 (NHERF1), 200 metformin, 282, 438, 458–9 Mitogen activated protein (MAP), 630 Na+/K+ ATPase, 346–9 methacholine, 504, 506, 507 Mitogen activated protein kinases operation mode, 349 methadone, 124, 128–9, 573 (MAPK), 133, 147–53, 195, 199, pharmacology, 348 methamphetamine, 124, 370, 373, 485 576, 577, 581, 582, 583 structure, 348 methotrexate, 257, 416, 418–19, 629, 636, pharmacological inhibitors, 151–3 Na+/K+/Cl-cotransporter (NKCC), 356–8 679–81, 684 specificity, 150–151 pathology, 357 methylation, 67, 136 subtypes, 147–50 pharmacology, 358 methyldopa, 484, 492 mitoxantrone, 416, 422–3 structure, 357 methylhistamine, 525, 527 molecular modeling, 692–3 nalbuphine, 573 methyllycaconitine, 502 monoamine oxidase (MAO), 370, 434, 521 nalidixic acid, 642, 649 methylphenidate, 372, 485 MAO A, 511, 513–4, 518 naloxone, 129, 574, 580, 684 methyltestosterone, 281 MAO B, 525 naltrexone, 128–9, 574

0002534462.indd 725 5/11/2015 2:38:21 PM 726 Index

namitecan (ST1968), 421 nicotine, 124, 126, 501, 503–4 norfloxacin, 642, 680 nanodrugs, 18 replacement therapies, 128–9 norgestimate, 280 nanomedicine, 43 nifedipine, 35, 49, 71, 326–5, 682–3 nortriptyline, 57, 259, 515, 517–18 nanotube, 466 nikkomycins, 651–2 Nuclear Factor of Activated T lymphocytes naphazoline, 492 nilotinib, 424 (NF-AT), 251 naproxen, 71, 606, 611–13 Nim 811, 436 nucleosides, 553 naratriptan, 517 nimesulide, 611–13 nucleosome, 246 natalizumab (Tysabri), 233, 628, nimotuzumab, 239 nucleotides, 553 636, 695 nipecotic acid, 365, 368, 374 cyclic, 176, 178, 179, 183, 317, nebivolol, 492–3 nitric oxide (NO), 497, 511, 516, 523, 561 339, 341 necrostatin-1, 413 atheroscelrosis, 602 nucleus basalis of Meynert, 495 nelfinavir, 71, 387, 393, 693 biochemistry, 599–602 neomycin, 14, 642, 647 biosynthesis, 597–9 observational studies, 710 neostigmine, 35, 49, 500, 503 NO synthases, 597–9 occupancy neprilysin, 381, 386–7 NO synthases control by NO, 599 theory, 101 nerve growth factor (NGF) see growth cardiovascular system, 602–3 threshold, 107 factor central and peripheral nervous systems, ocular dryness, 559 netilmycin, 642 603–4 oil-water partition coefficient, 24, 32 neurexins, 473 cytochrome c oxidase inhibition, olanzapine, 516–18 neuroadaptation, 121–3, 126–7 600–601 oligonucleotides, 285–91 neuroligins, 473 guanlyate cyclase activation, 599–600 antisense, 286 neuromuscular blockers, 504, 506 hypertension, 602 delivery, 287 neuromuscular junction see junctions and immune system, 605 inhibition of miRNA, 286 neuropeptides, 468–9, 565–71 metabolic diseases, 603 LNA, 286, 289 colocalization, 367 metabolic syndrome, 603 2’-O-Alkyl-ribonucleotides, 289 encoding genes, 566 microRNAs, 602 pharmacokinetics, 289 functions, 569 nitrates tolerance, 606 pharmacotoxicology, 289–90 neuropeptide Y (NPY), 567–70 nitrate vasodilators, 606 phosphoroamidates, 289 processing, 566–7 nitric esters, 606 phosphorotioates, 289 receptors, 567–8 pharmacology, 606–7 PNA, 289 secretion, 567–8 respiratory system, 603 structure, 288 storage, 567–8 skeletal muscle, 604–6 toxicology, 289–90 synthesis, 566–7 S Nitros(yl)ation, 601–3 omalizumab, 628, 636 therapeutic potential, 569 stimulators of cGMP action, 606 omeprazole, 15, 70, 71, 259, 347, 351, neuropharmacology, 474 systemic and organ effects, 602–606 682, 685 neurosteroids, 533–4, 536, 540 nitrofurans, 643 ondansetron, 71, 263, 338, 517 allopregnanolone, 536, 540 nitrofurantoin, 643 operant conditioning, 123 tetrahydrodeoxycorticosterone nitroglycerin, 35, 38, 42, 49, 57, 597, opiates, 124, 126, 190, 573 (THDOC), 532, 540 602, 606 addiction, 583 neurotensin, 482, 525, 571 nitroimidazoles, 643 endogenous peptides, 572 neurotoxins, 168, 475–6 nizatidine, 527, 528 endogenous peptides distribution, 574 neurotransmitters, 6, 57, 93, 94, 111, 113, NMDA receptors see glutamate receptors opioid receptors, 575 122, 175, 177, 186, 190, 194, N-methylhistamine, 521 cardiovascular effects, 579 321, 331, 361–60, 417, 465–72, N-methylimidazoleacetic acid, 521 distribution and effects, 576–80 475, 484, 500, 522, 538, 553, N,N,diethyl-2-[4-(phenylmethyl) effects on food intake and body 561, 567–8, 604, 608 fenoxiletanamine] (DPPE), 523 temperature, 580 receptors, 468 nociceptin, 572, 574, 575 effects on GI tract, 579 transporters nociception, 558 effects on immune system, 580 dependence from ions, 362 nocodazole, 474 GPCR, 575–6, 580, 582, 584 family evolution, 367 noncholinergic, nonadrenergic modulation of nociceptive H+-dependent, 372–3 (NANC), 553 transmission, 576 Na+/Cl−-dependent, 364–72 nonsteroidal anti-inflammatory drugs NOP, 575, 584 Na+ K+-dependent, 361–4 (NSAIDs), 611–13 respiratory depression, 579 structure and function, 362 adverse effects, 611, 613 signal transduction, 575 neutral amino acid transporter, 513 coxibs, 611–13 opioid system, 572–84 nevirapine, 655, 660, 705 therapeutic activities, 611, 613 organic nitrates, 35 NF-kB, 251, 410, 428, 632 traditional, 611–13 organic phosphates, 338 nicorandil, 335 noradrenaline, 156, 360, 366, 371, 471, ornithine transcarbamilase (OCT) nicotinamides, 335 478, 484–5, 492, 514, 517, 567 deficiency, 304

0002534462.indd 726 5/11/2015 2:38:22 PM Index 727

orthosteric, 102–3 penicillin G, 36, 41, 642 phentolamine, 492 binding sites, 103 penicillins, 56, 642, 645 phenylalkylamines, 320, 328, 330 ligands, 102 discovery, 14 phenylbutazone, 56, 612 oseltamivir, 656, 657 pentamidine, 338 phenylephedrine, 492 osteoblasts, 513, 563 pentavalent antimonial, 338 phenyl histamine, 527 osteoclasts, 384, 563 pentazocine, 49, 573 phenylpropanolamine, 485, 492 o-sulfate, 514 peptide maturation, 386 phenytoin, 51, 320, 325 oxaliplatin, 416, 418 peptidergic neurons, 568 phosphatidylcholine (lecithin), 499 oxandrolone, 281 peptidergic transmission, 568–9 phosphatidylinositol 3-kinase (PI3K), oxaprozin, 612 perhexilline, 438 155, 194 oxaxilidinones, 642, 648 peroxisome proliferator-activated receptors phosphodiesterases, 196 oxidation, 62 (PPAR), 272, 282, 446–8 phosphodiesterase-4, 639 P450-independent mixed oxidations, 65 pharmacological modulation, 447 phospholipases, 609 oxidative phosphorylation, 437 PPARα, 282, 438 phospholipase C, 196–8 oxotremorine, 507 PPARα agonists: fibrates, 447 phosphomycin, 642, 645 oxprenolol, 492 PPARα/γ agonists, 283, 448 photosensitization, 670 oxycodone, 573 PPARα regulated genes, 282 physiologically based pharmacokinetics oxymetazoline, 492 PPARβ, 282 (PBTK)/toxicokinetics (PBPK) PPARγ, 282, 438 modeling, 673 p21, 406 PPARγ agonists: thiazolidinediones, physostigmine (eserine), 187, 499, 505 p38, 150, 153, 413, 639 282, 447–8, 460 picrotoxin, 531, 534 p53, 406–7, 411–13 PPARγ regulated genes, 282 pigmentous retinitis, 192 p75, 115 personalized medicine, 712 pilocarpine, 504, 506, 507 paclitaxel, 263 pertussis toxin, 193–4 pimozide, 338 pactimibe, 449 pertuzumab (Perjeta), 214 pinacidil, 335 pain, 12–13, 36, 38, 100, 123, 163, 260, p-glycoprotein, 263, 683, 685 pindolol, 493 313, 320, 324–5, 331, 339, 461, pH, 24 pioglitazone, 282, 440, 447, 458, 460 475, 510–511, 528, 547, 549, gastric, 34 piperacillin, 642 562, 565, 570–571, 573–4, pharmaceutical form, 696 pirenzepine, 504, 506–7 578–9, 582, 584, 590–601, 612 pharmaceutical interactions, 685 piroxicam, 612 inflammatory, 562 pharmacoeconomics, 5 pituitary GH-secreting adenomas, 194 neuropathic, 562 pharmacogenetics, 5, 256–67 placebo, 5 palivizumab, 239, 695 future trends, 266 placental barrier, 29–30 palmitoylation, 137 pharmacogenomics, 5, 256 plasma concentration, 39, 73–88 palonosetron, 517 pharmacognosy, 5 fluctuations, 79–80 pancreatic cells, pharmacological pharmacokinetics, 5, 694–5, 700–707 free drug, 50–51, 82 stimulation of β-cell, 458–9 clinical, 704–5 peak, 75 pancuronium, 504, 506 formulations, 706 protein bound, 50–51 panitumumab, 214, 695 generics, 706 steady state, 77–8 para-aminohippuric (PAH), 56 in vitro, 700–707 time course, 73–81 para-aminosalicylic acid (PAS), 642 in vivo, 700–707 time-to-the-peak, 39, 74–5 Paracelsus, 10 pharmacology plasmamembrane Ca2+ ATPase, 351–2 paracetamol, 62, 612, 638, 682 arab, 9 plasma proteins, 50–51, 81 parachlorophenylalanine, 513–14 biotechnology, 15 binding to, 50, 59, 81 parathion, 500 clinical, 5 plasminogen, 396–9 Parkinson’s disease, 480–486, 507, 560 egiptian, 8 plasminogen activator, 397–6 drugs, 494, 498, 506, 507 hebrew, 8 inhibitor, 396 paroxetine, 366, 515 medieval, 9 platelets, 226, 228–9, 232 partition coefficient, 23–6, 29, 32, 36, renaissance, 10 activation, 228–9 38–41, 46, 56 romans, 9 platinum compounds, 418 Pasteur, L., 12 safety, 694, 696 p75NTR, neurotrophin receptor, 167 patch clamp technique, 186, 372 twelve century, 15 poisoning, 9, 421, 500, 505–6, 584, 684 patent, 691–2 pharmacotherapy, modern, 14–15 poly-(ADP-ribose)-polymerase pazopanib, 214 phencyclidine, 124, 126 (PARP), 549 PC12 cell differentiation, 169 phenobarbital, 4, 49, 57, 69, 70, 85, 273, polyamines, 653 pefloxacin, 642, 649 283, 680, 682 polyenes, 654 pemoline, 485 phenol-O-methyltransferase (POMT), 67 polymixins, 525, 642, 650 penciclovir, 655–6 phenoxybenzamine, 486–7, 491–2 polymorphisms, 182, 192, 257–66, 363, penicillin binding protein, 645 phentermine (phen), 513 584, 633

0002534462.indd 727 5/11/2015 2:38:22 PM 728 Index

polypeptides, 642 promoter, 110, 244, 272, 600, 627, 632 P2X, 557–8, 560–564 posizolid, 642 distal, 246 P2Y, 557–63 post-synaptic density protein 95 downstream element (DPE), 244 purines, 553–64 (PSD-95), 473 minimal, 244 pyridostigmine, 500, 505 posttranslational modifications, proximal elements, 244–6 pyridoxal-phosphate-6-azophenyl-2’,4’- pharmacological modification, upstream element (UPE), 246 disulphonic-acid (PPADS), 130–138 proopiomelanocortin (POMC), 567, 570 557, 559 potassium (K+) channels, 331–9, 456 propafenone, 71, 325 pyrimidines, 335, 553, 555

2 transmembrane segments, (KATP), propeptide, 566 pyruvic dehydrogenase, 438 332–5 propranolol, 58, 325, 492 composition, 332 prostanoid receptors, 167, 618–20 quantal release, 470

pharmacology, 332 PGD2 receptors, 618 quantitative structure-activity relationship

SUR composition, 332 PGE2 receptors, 619 (QSAR), 673, 693

4 transmembrane segments, 336 PGI2 receptors, 619 quetiapine, 338, 516–17

6 transmembrane segments TXA2 receptors, 619–20 quinidine, 325, 338, 680–681 voltage gated (VGKC), 336–9 prostanoids, 608–614 quinine, 338

EAG type, 336 PGD2, 609, 614 quinolones, 338, 642, 649

ERG type, 336 PGE2, 609, 614–15 quinpirole, 490

LQT type, 338 PGF2, 609, 614 quinupristin-dalfopristin, 642

Shaker type, 336 TXA2, 609, 613–14 7 transmembrane segments (7TM), prostanoid synthase, 613–15 Rab, 156 339 prostaglandin D synthase, 614 Rac, 156 Ca2+-activated K+ channels (BK prostaglandin E synthase, 614–15 radezolid, 642 channels), 340 prostaglandin F synthase, 614 RAF, 152 potassium conductance, 557, 560, 562 prostaglandin H synthase, 610–613 raloxifene, 279, 281 potency, 100–101, 103–4, 106, 108 prostaglandin H synthase pathway, 610 R-(α)-methyl-histamine, 527 PP1 phosphatase, 406 prostaglandin I synthase, 614 Ran, 154–7 pralidoxime, 500 thromboxane synthase, 613–14 ranitidine, 527–8 pralnacasan, 387, 391 protease domain, 397 Rap, 156, 157 pramicidins, 651 protease inhibitors, 379, 382, 392–3, 399, rapamycin, 263, 424, 627, 630, 632–3 prasugrel, 262, 561 655, 657, 660 rapsyn, 176 pravastatin, 440 proteases, 379–93, 521, 525, 567, Ras, 154–6 prazosin, 108, 491 658, 660 Ras-dependent transduction pathway, precautionary principle, 676 proteasome, 387–8 209–10 precocious puberty, 192 inhibitors, 425 Ras protein, 155–6, 163 prednisolone, 187, 280 protein kinases, 131–2 REACH regulation, 673 prednisone, 280, 628–9 activation, 132 reboxetine, 366, 486 pregnane X receptor, 272–83 5’ AMP-activated protein kinase receptor, 5, 93, 109–20 regulated genes, 283 (AMPK), 459–60 autoreceptor, 176–7, 482, 488, 491, 501, pre-initiation complex (PIC), 243–6, calcium/calmodulin-dependent protein 512, 515–16, 520, 538 249–50 kinase II, 131 cell membrane, 6, 110 preladenant, 561 protein kinase A (PKA), 131–2, 184, complex, 94 prenylation, 136, 163 196, 523 constitutively active, 107–8 prepropeptide, 566 protein kinase C (PKC), 184, 197 cytoplasmic duality of receptors, 166 Priestley, J., 11 protein phosphatases, 132–3 density, 97, 108 pristinamycin, 642 protein phosphorylation, 130–135 desensitization, 7 probenecid, 49, 56–7, 680, 684 protein tyrosine phosphatases, 434 down regulation, 7, 117–18 probucol, 338 proton pump inhibitors, 3, 15, 347, 351 endocytosis, 116 procainamide, 57, 262, 325, 338 prucalopride, 518 frizzled receptors, 167 procaine, 36, 65, 324 P-selectin, 523 heteroligomeric receptor, 177–8 procyclidine, 506–7 pseudoephedrine, 485, 492 homomeric receptor, 177–9 prodrug, 61 pseudomonic acid, 642 hypersensitivity, 117 progesterone, 263 p66Shc, 434 intracellular, 6, 110 progesterone receptor, 272–81 psilocybin, 124 localization, 116–17 antagonists, 278 psoriasis, 564 modulation of the activity, 109–19 progestins, 270, 280 purinergic receptors, 553–64 nuclear, 110, 166 prohormone convertases, 567 P1, 556–64 nuclear classes 1-3, 272 prokineticin 2 (PK2), 569, 571 P2, 556–64 nuclear signal transduction, 110

0002534462.indd 728 5/11/2015 2:38:22 PM Index 729

orphan receptor, 191, 560 retinoids, 282 Scheele, K.W., 11 postsynaptic receptor, 175 all trans retinoic acid, 282 Schmiedeberg, O., 12 presynaptic receptor, 175 Rheb, 156 scopolamine, 42–3, 498, 504, 506–7 reserve, 106 rheumatoid arthritis, 564 secretory granules, 469 spare receptors, 106 Rho, 154–6, 194 secretory vesicles, 168, 380, 385, 469, 474 subtypes, 99 rhodopsin, 189–90, 194 sedative hypnotics, 124 synthesis, 117 Rho family GTPases, 158–62 seizures, 562 theory, 101–5 rifabutin, 642 selectin, 114, 225–227 traffic, 117 rifamicins, 642, 646 signal transduction, 231–2 two-state receptor model, 107 rifampicin, 642 selective serotonin reuptake inhibitors upregulation, 118 rifaximin, 642, 646 (SSRI), 511, 513, 515, 518 receptor classes, 109–10 riluzole, 336, 549–50 selumetinib, 152 cytochines, 114 rimonabant, 590–591 Semmola, G., 12 death (DR), 115, 408 risk sensitization, 123, 127 decoy, 116, 236 assessment, 673 serine proteases, 380 dominant negative, 237 characterization, 668 serotonin (5-hydroxytryptamine, 5-HT), G protein coupled, 112 risperidone, 494, 517 190, 509–19 guanylate ciclase activity, 114 ritanserin, 517 cardiovascular system, 511–13 kinase activity, 113 ritodrine, 492 drugs, 516–18 ligand gated, 111 ritonavir, 263, 387, 683 gastrointestinal and genitourinal lipoprotein, 116 rituximab, 239, 427, 635 sistems, 513 toll-like, 115 rivastigmine, 500, 505 nervous system, 509–11 tumor necrosis factor (TNF), 115 rizatriptan, 516 release and reuptake, 514–15 receptor identification, 96 RNA-induced silencing complex (RISC), synthesis, 513–14 pharmacological profile, 96 285, 292 transporter, 511, 513–15 saturability, 96 RNA interference, 284–5, 426 serotonin receptors, 515–18 selectivity, 95–6 RNA polymerase II, 243 5-HT1, 511–13, 515–17 specificity, 96 rocuronium, 504 5-HT2, 511–13, 515–17 receptor-interacting protein-1 (RIP-1), rofecoxib, 611–13 5-HT3, 512, 513, 515–18 410, 413 Roger, 12 5-HT4, 511, 513, 516–18 receptor-interacting protein-3 (RIP-3), rokitamycin, 642 5-HT5, 512, 516 410, 413 roselipin, 446 5-HT6, 512, 516–18 receptor interactions, 93–7 rosiglitazone, 282, 283, 440, 447 5-HT7, 511–12, 516–18 hydrogen bonds, 94 rosuvastatin, 440–441 serotonin transporter (SERT), 369 hydrophobic interaction, 94 roxithromycin, 642 function, 370 ionic bonds, 94 ryanodine receptor (RYR), 143–4 pharmacology, 370 irreversible, 95 sertindole, 338, 517 reversible, 95 S-adenosylhomocysteine (SAH), 555–6 sertraline, 366, 515 van der Waals interactions, 94 S-adenosyl-l-homocysteine, 525 setrons, 517 receptor states S-adenosylmetionine (SAM), 555 severe combined immunodeficiency active, 107 S-adenosynil-l-methionine, 525 (SCID), 304–5 inactive, 107 salbutamol, 492 SH2 domains, 113, 158, 206–9, 211, 230 reduction, 65 salernitan medical School, 9 Shild graph, 103–4 regenerative medicine, 296, 300–303 salicylates, 56, 461, 612, 681 side effects, 7 regorafenib, 214 salinosporamide A (NPI-0052), 426 signaling cascades, 168 remifentanil, 573 salmeterol, 492 signal transducer and activators of renin, 330, 488, 489, 491, 493, 557, 559, 660 salsalate, 458, 461 transcription (STAT), 208, renin-angiotensin system, 330 Salvarsan, 13 212–13, 251, 636 repaglinide, 332–3, 458 saquinavir, 387, 393, 685 signal transduction repetitive administration, 75–80 sarcoplasmic-endoplasmic reticulum Ca2+ inside-out, 229 research stages, 692 ATPase (SERCA), 142–3, 352–3 outside-in, 229–31 research strategy, 691 distribution, 351 sildenafil, 597, 606 reserpine, 373, 475, 514 pharmacology, 353 silencer, 246 retigabine, 320, 335, 339 sarin, 500 simvastatin, 264, 440–441, 450 retinoic acid receptor (RAR), 272–82 sarpogrelate, 517 single nucleotide polymorphisms translocation, 282 satellite cell, 301 (SNP), 257 retinoid acid receptor, 9-cis retinoic acid scale-up, 697 siRNA, 284–6 receptor (RXR), 272 Scatchard transformation, 98 in clinical trials, 291

0002534462.indd 729 5/11/2015 2:38:22 PM 730 Index

sirolimus, 263, 424, 627, 630, 632–3 multipotent, 299 pruning, 473 SIRT1, 249 pluripotent, 298 small clear synaptic vesicles (SSVs), 567 sirtuins, 249 steroids, 633–5 tripartite, 466 skeletal muscle, 301, 332, 334, 340, 352, receptor, 166, 167 vesicles, 465 446–7, 477, 488, 604 streptogramins, 642 synapsin, 471 sleep–wake cycle, 509, 511, 513 Streptogramin, 640, 641, 645–46 synaptogenesis, 472 SMAC, 411 streptomycin, 642, 647 synaptopathies, 468 small G proteins, 154–65 striatal interneurons, 562 synaptotagmin, 471 modulation, 159–64 substance P (SP), 525, 565, physiological roles, 155 567, 570 T25, 675 posttranslational modification, 157, 163 substances abuse, 124 tabun, 500 regulatory proteins, 157–9 subunit, 176–9 tachykinins, 565–7 structure, 154 topology, 176–9 tacrine, 500, 526 subcellular localization, 157 succinylcholine, 501, 504, 506 tacrolimus (FK-506), 71, 222, 253, 263, smooth muscle contraction, 118, 156, 158, sufentanil, 573 338, 627, 630–633, 679–80, 682 215, 320, 327, 510, 523–4, 527, sugammadex, 506 talavancin, 642, 650 538, 558–9, 563, 579, 602–3, suicide inhibition (inactivation), 72 tamoxifen, 71, 248, 261, 276, 279, 281, 609, 614, 617–19 sulbactam, 642 426, 523, 682 snake venum toxin, 476 sulfadiazine, 642 tamsulosin, 492 SNARE proteins, 329, 470–471, 475, sulfamethoxazole, 642 TATA-box binding protein (TBP), 243–4 501, 505 sulfation, 67 taurine, 367 sodium (Na+) channels sulfinpyrazone, 612 taxol, 413, 416 voltage gated (VGSC), 322–6 sulfonamides, 51, 642, 649 tazobactam, 642 α-subunits, 322 sulfonylureas, 320, 333, 455, 458–9 t‐butyl‐bicycle‐phosphorothionate β-subunits, 322 sulfotransferase, 514 (TBPS), 532 cellular organization, 322 sulpiride, 489, 490 tea, 562 classification, 323 sumatriptan, 516 tedisamil, 325, 338 functional properties, 322 sumo, proteins, 133 tedizolid, 642 molecular structure, 322 sumoylation, 133–4 tegaserod, 518 pharmacology, 323 conjugating enzymes, 133 teicoplanin, 642 sodium-glucose linked transporters consensus motifs, 133 telavancin, 642 (SGLTs), 453 SENP enzymes, 133 telbivudine, 659 inhibitors, 460–461 sunitinib, 214 tele-methylhistamine, 525 SGLT2, 458 superoxide anion, 433 tele-methylimidazole acetic acid, 525 solifenacin, 506–7 superoxide dismutase, 63 telomeres, telomerases, 426 sorafenib, 152, 214–15, 426 suramin, 557, 559 temozolomide, 417–18 sordarins, 653 survival factor inhibitors, 423 tenoxicam, 612 sotalol, 320, 325, 338, 492 HSP90 inhibitors, 425 terazosin, 492 sparfloxacin, 338 PI3K/akt/mTor inhibitors, 424 terbutaline, 492 specific flux, 27, 52 raf/mek/erk inhibitors, 425 terfenadine, 263, 338, 527 spin-off, 689 Tyr-kinase inhibitors, 424 terodiline, 338 spiramycin, 338, 642 sushi regions, 538 terpenic derivatives, 335 spironolactone, 280, 676 sympathetic system, 478–9 testosterone, 35, 192, 263 squalene synthase inhibitors, 442–3 anatomical organization, 478 tetanus toxin, 329, 381, 475 pharmacological activity, 443 cardiovascular effects, 479 tetrabenazine, 373, 514 squalestatin, 440, 443 noncardiovascular effects, 479 tetra-chlorodibenzo-p-dioxin (TCDD), 666 Src, 230 sympathomimetic drugs, 485, 490 tetracyclines, 642, 647 Src kinase, 199 synapse, 465–76 tetrahydrocannabinol (THC), 590 stanozolol, 281 active zone, 140, 465, 469 tetryzoline, 492 start-up, 787 chemical, 465 thalidomide, 14, 627, 630 statin-induced myopathy, 264 cleft, 465 theobromine, 554, 557, 562 OAT1B1 polymorphisms, 264 electrical, 465 Theophrastus, 8, 10 statins, 15, 70, 137, 157, 162–3, 264, excitatory synapse, 469, 547 theophylline, 554, 557, 561–2 441–3, 679, 683–4, 691 immunological, 116 therapeutic regimen, 83–7 pharmacological activity, 441 inhibitory synapse, 469 therapeutic window, 21, 39, 54, 80, STAT protein, 208, 212–13, 251, 636 large dense-core vesicles (LDCVs), 87, 705 stem cells, 296–9 566–8 therapy, personalized, 17 embryonic, 298 plasticity, 472–4 thiazide diuretics, 56, 347

0002534462.indd 730 5/11/2015 2:38:22 PM Index 731

thiazol ethylamine, 527 toxic agents, 672–4 Trk neurotrophin receptors, 167 thiazolidinediones, 282, 438, 447–8, 460 annual production, 673 troglitazone, 440, 447 thiocarbamates, 652 mechanism of action, 672 tropisetron, 517 thioformamides, 335 mixtures, 674 tryptophan hydroxylase, 513 thioguanine, 262, 419 toxicity TSC2, 170 thioperamide, 526–7 dose response, 666 tubocurarine, 14, 49, 411, 502, 504, 506–7 thiopurine methyltransferase (TPMT), 262 evaluation new chemicals, 669 tumor necrosis factor (TNF), 408, 410, thiopurine-S-methyltransferase existing chemicals, 669 411, 413 (TSMT), 67 exposure assessment, 667 TNFα antagonist, 636 thioridazine, 338 genotoxicity, 670 TNF receptor (TNFR), 115, 410, 411 thiorphan, 386–7 irritation, 670 tyramine, 65, 486, 680 threshold of toxicological concern phototoxicity, 670 tyrosine kinase, 207–15 (TTC), 675 reproduction, 671 cytoplasmic, 211–12 thrombin, 190–193, 195 sensitization, 670 inhibitors, 213–15 thrombosis, 561 test guidelines, 672 non-receptor, 211 thromboxanes, 263, 605, 618 toxicokinetics, 671 receptors, 207 thyroid adenomas, 192, 194 toxicology, 5, 665–77, 697–8 signal transducers, 208, 210 thyroid hormones, 281 environment, 674 tyrosine phosphatases, 212 receptors, 272–81 risk/benefit ratio, 7 tyrphostin, 164 triiodothyronine, 281 therapeutic index, 7 thyroid-stimulating hormone (TSH) tramadol, 260, 573 ubiquitination, 134 receptor, 190–195 tramazoline, 492 conjugating enzymes, 134 thyrotropin-releasing hormone (TRH), transcription urapidil, 492 190, 194, 481, 501, 567 regulation, 243 uric acid, 57 ticagrelor, 560–561 regulators, 275 uridine, 556 ticarcillin, 642 synthetic modulators of transcription uridine diphosphate (UDP), 553–64 ticlopidine, 71, 560–561, 682 activation, 254 galactose, 553–64 tight junctions see junctions transcriptional control genes involved in glucose, 553–64 timolol, 71, 325, 492 lipid metabolism, 446 uridine-5’-triphosphate (UTP), 553–64 tiotidine, 526–8 transcription repressors, 244, 246, 276 urokinase (u-PA), 395–9 tiotropium, 506 transferrin, 26 pro-uPA, 398 tirofiban (Aggrastat), 233 translocator protein (TSPO), 535 receptor (u-PAR), 399 tissue plasminogen activator (tPA), transmission ustekinumab, 628, 636, 695 395–7 extra-synaptic, 568 TNFR1‐associated death domain volume transmission, 468 vagusstoff, 496 (TRADD), 410 wiring transmission, 468 valdecoxib, 611–13 TNF‐related apoptosis‐inducing ligand transplantation, 299 valproic acid, 49, 57, 325, 530, 682 (TRAIL), 410, 413 allogeneic, 299 vancomycin, 642–3, 645 tobramycin, 642, 647 autologous, 299 vandetanib, 214 tocainide, 320, 325–6 transporters varenicline, 128–9, 504, 507 tocilizumab, 628, 636 ATP-dependent, 345–6 vascular adhesion molecules (VCAM 1), tolazoline, 492 ATP-independent, 346 226, 228 tolbutamide, 71, 259, 332, 679, 681–2 endocytosis, 361 vasoactive intestinal peptide (VIP), tolerance, 7, 122–3, 125, 127, 572, for excitatory amino acids, 361 569, 570 580–583 traffic, 361 vasopressin, 158, 190, 482, 523, 569 adrenergic receptors, 493 trastuzumab (Herceptin), 214, 417, vasopressin receptor, 190, 192 antibodies, 635 427–8, 695 Vauquelin, L.-N., 12 GABA receptors, 534–5 triamcinolone, 280 vecuronium, 506 glucose, 455, 560 tricyclic antidepressants, 366, 370, vedolizumab, 628, 636 immunodrugs, 630 511, 515 vemurafenib (PLX4032), 152, 417, 425 metabolism, 101 trifluoromethylhistamine (α-), 525 verapamil, 263, 325, 682 nitrates, 606 triglyceride biosynthesis, 440, 444–5 vernakalant, 336–7 opioids, 572, 580–582 trimetaphan, 504, 506 vesamicol, 373–4, 475, 500 toll-like receptors (TLR), 1–5, 115 trimethoprim, 642, 649 vesicular transporters, 361, 372–4 tolmetin, 612 trimethoprim/sulfamethoxazole, 338 acethylcholine (VAChT), 374 tolterodine, 506–7 tripelennamine, 527 GABA (VGAT), 374 topotecan, 421–2 triprolidine, 527 glycine, 374 torcetrapib, 449–50, 711 triptans, 516 monoamines (VMAT), 373

0002534462.indd 731 5/11/2015 2:38:22 PM 732 Index

vidarabine, 656 volociximab (M 200), 233 xenobiotics, 61–2, 65, 71, 258, 263, 273, viloxazine, 366 volume neurotransmission (VNT), 283, 682–3 vinblastine, 263, 413, 420 568 activated receptors, 26 vincristine, 263, 413, 420, 474 von Bezold-Jarisch reflex, 512 xylometazoline, 492 viral proteases, 392 Von Linné, C., 11 viramidine, 658 yohimbine, 492 Virchow, R., 12 warfarin, 51, 71, 84, 260, 266, 679–82, vitamin A, 282 685, 705 zanamivir, 657

vitamin B6 (pyridoxal phosphate), 524 whole body autoradiography, 703 zatebradine, 321, 341 vitamin D, 281–2 withdrawal, 123, 125, 127, 574, 582 ziconotide, 320, 331 cholecalciferol, 281 Wnt receptor agonists, 167, 170 zidovudine, 655 ergocalciferol, 281 ziv-aflibercept (Zaltrap), 214 vitamin D receptors, 272–82 xanomeline, 504, 506 zolmitriptan, 516 polymorphism, 281 xanthines, 557, 597 zotasetron, 516–17 vitronectin, 228 xantumol, 446 zygote, 296

0002534462.indd 732 5/11/2015 2:38:22 PM