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`
`Joe] G. Hardmao
`Lee E. Limbird
`
`Perry B. Molinoff
`Raymond W. Ruddon
`
`Alfred Goodman Gihnao
`
`
`
`CFAD EXHIBIT 1016
`CFAD EXHIBIT 1016
`
`

`
`McGraw-Hill
`~
`A Division of The McGraw-Hill Companies
`
`Goodman and Gilman's THE PHARMACOLOGICAL BAStS OF THERAPEUTICS, 9/e
`
`Copyright© 1996, 1990, 1985, 1980, 1975, 1970, 1965, 1955, 1941 by The McGraw-Hill Companies,
`Inc. All rights reserved. Printed in the United States of America. Except as permitted under the United
`States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form
`or by any means, or stored in a data base or retrieval system, without the prior written permission of
`the publisher.
`
`1234567890 DOWDOW 98765
`
`ISBN 0-07-026266-7
`
`This book was set in Times Roman by York Graphic Services, Inc. The editors were Martin J.
`Wonsiewicz and Peter McCurdy; the production supervisors were Robert Laffler and Clare Stanley,
`and the cover designer was Marsha Cohen/Paralellogram. The index was prepared by Irving Conde
`Tullar.
`R.R. Donnelley and Sons Company was printer and binder.
`
`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in-Publication Data
`
`Goodman & Gilman's The Pharmacological Basis of Therapeutics. -9th ed. I Joel G. Hardman,
`Alfred Goodman Gilman, Lee E. Limbird.
`em.
`p.
`Includes bibliographical references and index.
`ISBN 0-07-026266-7 (hardcover)
`II. Gilman, Alfred.
`I. Goodman, Louis Sanford.
`1. Pharmacology.
`2. Chemotherapy.
`III. Hardman, Joel G.
`IV. Gilman, Alfred Goodman.
`V. Limbird, Lee E.
`[DNLM: 1. Pharmacology.
`2. Drug Therapy. QV 4 G6532 1995]
`RM300.G644 1995
`615' .7-dc20
`DNLM/DLC
`for Library of Congress
`
`95-36658
`
`

`
`CHAPTER 37
`
`AGENTS FOR CONTROL OF
`GASTRIC ACIDITY AND
`TREATMENT OF PEPTIC
`ULCERS
`
`Laurence L. Brunton
`
`is appmxlmatel
`The lifetime prevalence of peptic (gastric and duodeunl) ul r t/isea.v
`10%, and some physicians estimate that 50'%. of h alth ' imlividuals exji riem.· • heMllmm
`on a daily basis. The goals of therapy for ulce1; are relief fram pain, pmmulioll of II a l(cid:173)
`ing, and prevention of recurrence. Therapeutic strategies are 11im d m balancing aggres(cid:173)
`sive factors (gastric acid secretion, pepsin, Helicobacter pylori infection) against defen(cid:173)
`sive or cytoprotective factors (bicarbonate secretion, muc/1.\' secretion prostaglandin
`production). Drugs that reduce gastric acid secretion ( fl 2 hi,vlamiu receptor cmragonists
`and covalent inhibitors of the H+,K+ -ATPase of the pw·ietul ·ell) ejfecrively promore heal(cid:173)
`ing. Cytoprotective agents ( sucralfate, colloidal bismlllh, m1d th ' pro.\'laglarrdln agonist
`misoprostol) and antacids also are effective. Recurrence of ulcers is common, prompting
`long-term prophylactic use of H2 receptor antagonists and proton pump inhibitors. In pa(cid:173)
`tients who test positive for Helicobacter pylori, eradication of this bacterium with antibi(cid:173)
`otics promotes healing and reduces the likelihood of 1' curn n c (~<ce al. o Chapter 47). In(cid:173)
`hibitors of the H+,K+ -ATPase also are effective for gastm .wphngeal re.f1u di. ease and
`are preferred for erosive esophagitis. H2 receptor ant 1gonist · are u.<:ed
`' tenslvely for
`maintenance therapy in reflux. Minimizing use of nonsteroidal antiinflammatory drugs
`(Chapter 27), alcohol, and tobacco are important adjuncts to drug therapies of both peptic
`ulcer and acid reflux disease.
`
`Dyspepsia, in its many forms, has been mankind's com(cid:173)
`panion since the advent of bad cooking, overindulgence,
`and anxiety. Since one "is not altogether fit for the battle
`of life who is in perpetual contention with his dinner"
`(Meredith, 1859), considerable energy has gone into re(cid:173)
`lieving the symptoms of gastric upset and peptic ulcer dis(cid:173)
`ease.
`For centuries, neutralization of gastric acid with
`antacids provided the only relief from the pain of ulcers.
`Studies of the physiological control of acid secretion
`demonstrated that anticholinergic agents would blunt this
`proc , s. Th d vel pm ·nl hy B Ia k and o'lleu rue of ~m ­
`tagoni ' LS that act l Hr hi. lam ill ' rgi ' rccept
`provi.ded u
`m rc sp cific c1 . ~
`f inhibit r · o guslr.ic acid
`·cr tion.
`f
`M :re r• utly, the :ntbstl t:utcJ b m~jmidazol inhibitors
`} + K -ATPa
`:ffcr a very effectiv m ·an. ()f selective !
`for ll. iu e(cid:173)
`I eking 01 1 r l n pttmp !hot i · re pon lbl
`·r'tion I h parietal cell. Alll u h gastric acid hu~ doJ 1-
`
`inated thinking about peptic ulcer disease, appreciation of
`the m an by which tbe gastric muco. a normally pr T cts
`it ·~;;If (r >m damage has suggc ted additi nul. !hemp utic ap(cid:173)
`in luding tb u. of a variety o cyt protecti e
`pr a he
`agent! . h recogn3ti n f Lh r le of 11ellcoba ter p lor·;
`in causing g· .'Iritis (U'Id. in comrl buting ro ulcemti
`proces e. in the ·tom·tch and clu denum [lrovide
`tbe ther(cid:173)
`insighr th l el'rnill<!lino th1 bact riw would be a
`npeuti
`Ds fu l . lratcgy or promoting 1h h a:ling of ul cr ·~nd re(cid:173)
`venting th ir re urrence.
`Th paUlJ pbysi lorry of acid- pti d~ ea ·e may be
`1houghL of a un imb;1luncc b rweeJl aggressive factor
`(acid p p. in, H. 11 •!rJri infection and local mucosal de(cid:173)
`cretion
`bicarbonate mucus,
`nd
`fense!' ~th
`prostaglandins. Although treatment most often is directed
`at the reduction of aggressive factors, it can be directed at
`strengthening mucosal defenses of the stomach and the
`duodenum with so-called cytoprotective agents.
`
`9()1
`
`

`
`'JO.'.
`
`CAMP·dependent
`Pathway
`
`+
`
`•
`
`cell
`
`+
`superficial epithelial cell
`
`prazole
`
`H+ X-antacid s
`
`f(l [bt muth
`
`metronidazole)
`tetracyclin e
`cl arithromyci11
`moxicillin
`
`X-
`1-l. pylori
`mucous)
`
`Layer
`pH 7
`
`Lumen
`pH 2
`
`Figure 37-1. Physiological and pharmacological regulation of gastric secretions: the basis for
`therapy of peptic ulcer disease.
`
`This schematic shows the interactions among an endocrine cell that secretes histamine (enterochromaf(cid:173)
`fin-like [ECL] cell), an acid-secreting cell (parietal cell), and a cell that secretes the cytoprotective fac(cid:173)
`tors mucus and bicarbonate (superficial epithelial cell). Physiological pathways are in solid black and may
`be stimulated (+)or inhibited (- ). Physiological agonists stimulate transmembrane receptors: muscarinic
`(M) and nicotinic (N) receptors for acetylcholine (ACh); G, gastrin receptor; H2, histamine (HIST) recep(cid:173)
`tor; PG, prostaglandin E2 receptor. Actions of drugs are indicated by dashed lines. A blue X indicates a
`point of pharmacological antagonism. A light blue dashed line and an·ow indicate a drug action that mim(cid:173)
`ics or enhances a physiological pathway. Drugs currently used in treating peptic ulcer disease and dis(cid:173)
`cussed in this chapter are shown in dark blue. NSAIDs are nonsteroidal antiinflammatory drugs such as
`aspirin and are ulcerogenic. <D and® indicate possible input by cholinergic postganglionic fibers. (g) shows
`neural input from the vagus nerve. See the text for detailed descriptions of these pathways and of thera(cid:173)
`peutic interventions.
`
`Cellular Pharmacology of Gastric Secretion. The ra(cid:173)
`tionale for the use of agents that reduce gastric acidity is
`best understood in terms of the physiological regulation of
`acid secretion by the parietal cell. The three major path(cid:173)
`ways regulating parietal acid secretion include (1) neural
`stimulation via the vagus nerve, (2) endocrine stimulation
`via gastrin released from antral G cells, and (3) paracrine
`stimulation by local release of histamine from enterochro-
`
`maffin-like (ECL) cells. The major features of the regula(cid:173)
`tion of gastric acid secretion as they pettain to pharmacolog(cid:173)
`ical regulation are summarized schematically in Figure 37-1.
`Vagal stimulation and the action of gastrin (from duo(cid:173)
`denal and antral G cells) stimulate release of histamine
`from paracrine ECL cells or mast cells. The histamine in
`turn activates parietal cell H2 receptors that are linked to
`the stimulation of adenylyl cyclase, causing activation of
`
`

`
`CHAPTER J7 A<;ENTS FOR CONTROL OF GASTRIC ACIDITY AND TREATMENT OF PEPTIC ULCERS
`
`903
`
`timuli
`tb , cyclic AMP pathway. Oustrin Md mu. carinic
`o.lso may a dire tiy n ~11 pari ~tal cell Lo net vat Ca2+(cid:173)
`sl!"nsitiv pathways-. H2. recepto <.mt; g nist n l
`ttly block
`f l:ristami:u but a o blunt r ·ponse · t m; tyl(cid:173)
`u1
`fl'ecl'>
`cltt!Lille ltm.l gastrin, tJms contribwting to the retnarkablc
`clinical efficacy of these agents. These findings are con(cid:173)
`sistent with the view that acetylcholine and gastrin may
`stimulate parietal cells indirectly by causing the release of
`histamine from paracrine cells (see Figure 37-1). Activa(cid:173)
`tion of either the cyclic AMP- or Ca2+ -dependent pathway,
`or both, stimulates activation of H+ ,K+ -ATPase on pari(cid:173)
`etal cells, with its insertion into the apical membrane and
`leading to the formation of secretory canaliculi, with a con(cid:173)
`sequent secretion of H+ at rates between 20 and 40 mEq
`per hour. The result is an accumulation in the gastric lu(cid:173)
`men of H+ to a concentration of about 0.1 N. An increase
`in the permeability of the apical membrane to K+ and Cl(cid:173)
`accompanies activation of the proton pump.
`This scheme (Figure 37-1) provides a rationale for
`the modest inhibitory effects of anticholinergic agents, the
`impressive inhibition of acid secretion by H2 receptor an(cid:173)
`tagonists, and the effects of neutralizing gastric HCl with
`antacids on production and maintenance of gastric acidity.
`Clearly, covalent inhibitors of the H+ ,K+ -ATPase, such as
`omeprazole, inhibit acid secretion, the final common path(cid:173)
`way in gastric acid secretion. Prostaglandins, by inhibiting
`histamine-stimulated adenylyl cyclase activity in the pari(cid:173)
`etal cell, reduce activity through the histamine-evoked
`cyclic AMP-dependent pathway and thereby reduce acid
`secretion. Prostaglandins also stimulate the secretion of
`mucus and bicarbonate by adjacent superficial epithelial
`cells, contributing to the cytoprotective effects of endoge(cid:173)
`nous prostaglandins of the E series and to the protective
`effects of stable analogs of prostaglandins E 1, such as miso(cid:173)
`prostol. The importance of the tonic role of prostaglandins
`in cytoprotection is manifest by the ulcerogenic effects of
`nonsteroidal anti-inflammatory drugs (NSAIDs; see Chap(cid:173)
`ter 27) that inhibit prostaglandin synthesis. Bismuth, su(cid:173)
`cralfate, and carbenoxolone also enhance the cytoprotec(cid:173)
`tion afforded by the mucus layer.
`Since H. pylori may contribute to the defect in mu(cid:173)
`cosal defenses in some cases of peptic ulcer, the eradica(cid:173)
`tion of the bacterium constitutes yet another avenue of ther(cid:173)
`apy. The details of acid, pepsin, and mucus secretion in
`health and disease and the etiology of gastric ulcers have
`recently been reviewed (see Go1dschmiedt and Feldman,
`1993; and Soll, 1993).
`
`Therapeutic Strategies for Treatment of Peptic Ulcers
`and Gastroesophageal Reflux Disease. As indicated
`
`earlier, peptic ulcers arise due to an imbalance of acid se(cid:173)
`cretory mechanisms (so-called aggressive factors) and mu(cid:173)
`cosal protective factors, and their rational treatment is
`aimed at restoring that balance. The loss of balance be(cid:173)
`tween acid secretion and mucosal protective factors varies
`among peptic ulcer types. Type I ulcers, which occur high
`in the stomach, are associated with less or no acid hyper(cid:173)
`secretion, suggesting the importance of impaired mucosal
`protective factors in this clinical setting. 'Jype II ulcers, in
`contrast, include gastric ulcers and distal antral (pre(cid:173)
`pyloric) and duodenal ulcers and are associated with acid
`hypersecretion and impaired negative feedback effects of
`acidification on gastrin release and on continued acid se(cid:173)
`cretion.
`The causes of gastric ulcers include H. pylori infec(cid:173)
`tion, NSAIDs, and malignancy. If malignancy is identified
`on endoscopy and confirmed cytologically, surgical re(cid:173)
`moval is undertaken. If H. pylori infection is confirmed by
`culturing or by detection of circulating antibodies, appro(cid:173)
`priate combination antimicrobial therapy is instituted (see
`below). Otherwise, H2 receptor antagonists or H+ ,K+(cid:173)
`ATPase inhibitors are administered. Duodenal ulcers also
`can be caused by H. pylori or by NSAIDs, but rarely by
`malignancy. The possible role of H. pylori in ulcer devel(cid:173)
`opment is determined, and therapeutic agents are selected,
`as for gastric ulcers. However, as mentioned above, duode(cid:173)
`nal ulcers also can result from hypersecretion of gastrin,
`which can be assessed by evaluating fasting gastrin levels in
`patients unresponsive to other therapies for duodenal ulcers.
`
`Based on the understanding of the mechanisms contributing to ulcer
`development and particularly to gastric acid secretion, a variety of
`therapeutic strategies exist, including suppressing the aggressive fac(cid:173)
`tors contributing to acidification with the use of antacids, Hz recep(cid:173)
`tor antagonists, and H+ ,K+ -ATPase pump inhibitors, and fostering
`defensive factors, with the use of cytoprotective and prokinetic
`agents. These overall strategies are discussed below in terms of spe(cid:173)
`cific therapeutic agents.
`Gastroesophageal reflux disease (GERD) has been estimated to
`affect 10% of the population of the United States. Often it is treated
`by over-the-counter antacid preparations, as individuals with this con(cid:173)
`dition frequently do not seek medical assistance. The therapeutic ap(cid:173)
`proach is based on reduction of gastric acidity, increase of lower
`esophageal sphincter tone, and enhancement of esophageal clearance
`of refluxed material. Recommended lifestyle changes include elevat(cid:173)
`ing the head of the individual's bed by at least 6 inches, which re(cid:173)
`duces esophageal exposure to acid; cessation of smoking; consump(cid:173)
`tion of a bland diet devoid of citrus juices, coffee, and spicy food,
`which are direct irritants promoting GERD; avoiding bedtime meals;
`and avoiding certain medications, including theophylline, classic an(cid:173)
`ticholinergic agents, and progesterone, all of which delay gastric
`emptying and decrease lower esophageal sphincter tone. Should
`GERD persist, Hz receptor antagonists and proton pump inhibitors
`are the preferred therapies (see below).
`
`

`
`904
`
`SECTION VI DRUGS AFFECTING GASTROINTESTINAL FUNCTION
`
`HISTAMINE
`
`CIMETIDINE
`
`O
`
`II
`CHN02
`
`9CH~SCH2CH2 NHCNHCH3
`
`CtizN(CH3h
`RANITIDINE
`
`CH2SCH2CH2CNH2
`=<"
`II
`~
`NS02NH2
`y
`
`'
`
`N=C(NH2b
`
`FAMOTIDINE
`
`NIZATIDINE
`Figure 37-2. Structures of histamine and H2 receptor antago(cid:173)
`nists.
`
`H2 HISTAMINE RECEPTOR
`ANTAGONISTS
`
`H1 histamine receptor antagonists do not inhibit gastric
`acid secretion. The development in the 1970s of Hz re(cid:173)
`ceptor antagonists provided incontrovertible evidence for
`the importance of endogenous histamine in the physiolog(cid:173)
`ical control of gastric secretion (see Figure 37-1; see also
`Chapter 25) and transformed the treatment of peptic ulcer
`disease. The recent availability of Hz receptor antagonists
`as over-the-counter medicines likely will increase both
`their popularity and the necessity for physicians to under(cid:173)
`stand the therapeutic and adverse effects of these agents.
`
`Chemistry. The H2 receptor antagonists in clinical use are hista(cid:173)
`mine congeners that contain a bulky side chain in place of the ethyl(cid:173)
`amine moiety. Early representatives ofthe group, such as burimamide
`(Black, 1993) and cimetidine (the first compound released for gen-
`
`11narmncologital Properties. H:z. receptor antagonist
`comp titivcly inhibit th ir~tCJaction of histamine with B s
`l'ec ptor . . They ru:~ bighly elective and have little or n 2
`0
`ffe I c ti Ift r · ptors ()r Lher re · ptors. Although H r
`z e-
`ceptors are present in numerous tissues, including vascu-
`lar and bronchial smooth muscle, Hz receptor antagonists
`interfere remarkably little with physiological functions
`other than gastric acid secretion.
`Gastric Secretion. Hz receptor antagonists inhibit gastric
`acid secretion elicited by histamine and other Hz agonists
`in a dose-dependent, competitive manner; the degree of in(cid:173)
`hibition parallels the concentration of the drug in plasma
`over a wide range (Figure 37-3). The H2 receptor antag-
`
`cimetidine
`
`B c 3 or placeb!o b!etazole
`I-·(cid:173)wE
`0: LO 2
`0-r-
`CJ) tff
`.
`w- ~
`
`~_§_~ ~jl·~/ ' ' '
`l I;~
`
`Z..-...
`0 ,!;
`1-- E 3
`WLO
`C:-r-
`()~2
`W'
`CJ)~
`z ><
`CJ)~
`a.. c w ::::::1
`a.. -o
`
`• placebo
`• cimetidine, 200 mg
`cimetidine, 300 mg
`
`180
`
`21 0
`
`150
`120
`TIME
`(min)
`Figure 37-3. Effect of cimetidine on betazole-stimulated se(cid:173)
`cretion of acid (upper panel) and of pepsin (lower panel) in
`human beings. (Adapted from Binder and Donaldson, 1978 with
`permission.)
`
`

`
`CHAPTER 37 ACENTS JiOR CONTROL OF GASTRIC ACIDITY AND TH.EATI\IENT OF PEPTIC ULCERS
`
`905
`
`r ti n ·li ·ited by g<t trin and, to
`inhibit ncid ~'
`·~rs uJ!i
`1 '
`'
`· '
`'
`Ill·
`. r extent. by 1 :tus u.nnt agonms. t 1: •mporran1 t
`1
`1 estl,111 Hz r epL r antagoni ' Is inhihiJ ba~~l (fasting) and
`rr
`,~. .
`0 t-e
`•
`•
`d
`·b
`•
`tum:LI nci:d se ..-cuon. m1
`CCI conln ute. Ill a
`I .!Is
`lini ·al efli acy, H_ rec ptur antag -
`rlV .0 way t
`lhc·l'
`ll~l~~ a]. O r Ju 'C UCid 'CCI' l ion :O:limu!ated hy f( d. Sbum
`~~~dill!\• fundi
`cliJ:t: nt i n and vurio~s . phurm:Lco!o •ic. l
`.ents; this pr J 'lty, alth mgb not hmettl.ly . tgttdicaol
`~~~ 0 ih ·k 1 fie Is the vi t~11 rol of If tamine in m di<ll ·
`;1~g tJt effect:-! of divers
`.{inlUi i (s l' Figur> 7- 1 . The
`~ anUJ~ ni t. r ucc b th th alum of gnstJ·icjui • s -
`·retecl tllld ·its H. 1 con entrmion. The outpu t
`f pepsin,
`~hich is secreted by the chief cells of the gastric glands,
`enerally falls in parallel with the reduction in volume of
`!astric juice (see Figure 37-3). Secretion of intrinsic fac(cid:173)
`tor also is reduced; however, since this protein normally is
`secreted in great excess, absorption of vitamin B 12 usually
`is adequate even during long-term therapy with H2 antag(cid:173)
`onists. The concentration of gastrin in plasma is not sig(cid:173)
`nificantly altered under fasting conditions, although the
`normal prandial elevation may be augmented, apparently
`as a consequence of a reduction of the feedback inhibition
`of gastrin secretion that is normally provided by H+.
`Hz antagonists protect experimental animals from
`gastric ulceration induced by stress, pyloric ligation, as(cid:173)
`pirin, Hz receptor agonists, or cholinomimetics. H2 antag(cid:173)
`onists also counter peptic ulceration in human beings, as
`described below. They have no consistent effect on the rate
`of gastric emptying, the pressure of the lower esophageal
`sphincter, or pancreatic secretion.
`z-. 600
`Q.S
`f- ..§ 500
`<(-
`z E
`~ 'LiJ400
`:J{.)
`UJ ;; 300
`UJo
`~z 200
`Q<(
`-a:
`f-<( 100
`UJLU
`oo 0
`~_J
`0
`100
`80
`60
`40
`20
`0
`CREATININE CLEARANCE
`(Cic6 ml/min)
`F1'gur .l7-4. Relatirm s/lip bctwceu crentinine cle1mmce ( lc~),
`~lm tidine r:limirmtitm cleManr:e ( CIE) and nppJ'(1pr ir1t
`ime(cid:173)
`lidine (/o c rctlucfiun {11r p«<ieut witll lmpaired rtmal.fi~nctirm,
`IAdapsNl fmm Atkil1son aml mig. 1990. tvirh perm is io11.)
`
`nonrenal
`clearance
`
`100
`
`w
`Cf)
`75 0
`0
`-l
`<(
`::::>
`Cf)
`::::>
`u.
`25 0
`~
`0
`
`50
`
`Absorption, Fate, and Excretion. H2 receptor antago(cid:173)
`nists are rapidly and well absorbed after oral administra(cid:173)
`tion; peak concentrations in plasma are attained within 1
`or 2 hours. The oral bioavailability of nizatidine is ap(cid:173)
`proximately 90%, whereas first-pass hepatic metabolism
`limits the bioavailability of the other compounds to about
`50%. The half-time for elimination of cimetidine, raniti(cid:173)
`dine, and famotidine is 2 to 3 hours, while that of nizati(cid:173)
`dine is somewhat shorter-about 1.3 hours. Although sub(cid:173)
`ject to hepatic metabolism, these drugs are excreted in large
`part in the urine without being metabolized. Thus, renal
`impairment requires a reduction in dosage of these agents.
`However, hepatic metabolism contributes sufficiently to the
`clearance of ranitidine that the half-life of this agent is sig(cid:173)
`nificantly prolonged in patients with hepatic dysfunction.
`
`Renal tubular secretion of H2 receptor antagonists can be inferred
`from the fact that their renal clearance (CIE X percent renal excre(cid:173)
`tion; see Chapter I) exceeds the glomerular filtration rate. Because
`these agents are excreted from the kidney, their dosage should be re(cid:173)
`duced when treating patients with impaired renal function. Impaired
`renal function sometimes is difficult to assess in elderly patients,
`where a decreased skeletal muscle mass may result in normal serum
`creatinine levels despite markedly impaired renal function. The Cock(cid:173)
`croft and Garret equation can be used to estimate creatinine (Cr)
`clearance for calculating appropriate reductions in dosage:
`
`(140 - age) X (weight in kg)
`Clcr = -'----7-2-X-(s=-er_u_m_C_r -in=-m-g/_,d-,--1)=
`
`(37-1)
`
`This estimate is appropriate for men, but it should be reduced by 15%
`for women. Figure 37-4 provides a useful nomogram to guide the
`dosage choice for cimetidine when renal clearance is impaired. This
`nomogram is useful even in functionally anephric patients, since the
`nonrenal clearance is unimpaired in these individuals (Atkinson and
`Craig, 1990).
`
`Adverse Effects. A variety of adverse reactions have
`been ascribed to cimetidine and ranitidine, reflecting, in
`part, the very large number of patients who have been
`treated with these drugs. The incidence of reactions is low,
`and the reactions generally are minor. The low incidence
`is attributable in part to the limited function of H2 re(cid:173)
`ceptors in organs other than the stomach and to the poor
`penetration of these agents across the normal blood-brain
`barrier.
`The incidence of adverse effects with cimetidine is
`less than 3%; reactions are usually less intense and less
`frequent ( < 1%) or absent with normal clinical doses of the
`other H2 receptor antagonists. In many clinical studies, the
`incidence of side effects with H2 receptor antagonists is
`not greater than that for patients treated with placebo. The
`most common side effects of cimetidine are altered lacta(cid:173)
`tion, headache, dizziness and nausea, myalgia, skin rashes,
`
`

`
`!)()(,
`
`SECTIOl\ \'1 DRUGS AFFECTl~G (;ASTROINTESTll\AL FUNCTION
`
`and itching. The incidence of symptoms related to the CNS
`(somnolence, confusion) appears to be higher in the elderly
`and in patients with impaired renal function. Loss of li(cid:173)
`bido, impotence, and gynecomastia sometimes are ob(cid:173)
`served in patients who receive long-term therapy with high
`doses of cimetidine. These effects are presumed to be re(cid:173)
`lated to the ability of the drug to enhance the secretion of
`prolactin and to bind to androgen receptors, but they are
`rarely observed except following the high doses used to
`treat Zollinger-Ellison syndrome (see below). In addition,
`cimetidine inhibits the cytochrome P450-catalyzed hy(cid:173)
`droxylation of estradiol and increases the plasma concen(cid:173)
`tration of estradiol in men, effects not shared by the other
`agents. Case reports suggest that cimetidine occasionally
`causes hematologic effects (various cytopenias) and altered
`function of the immune system. Rarely, the use of cimeti(cid:173)
`dine has been associated with reversible bone marrow de(cid:173)
`pression, hepatitis, or anaphylaxis. Cimetidine appears to
`inhibit competitively the renal tubular secretion of creati(cid:173)
`nine and causes a small increase in its plasma concentra(cid:173)
`tion. Rapid intravenous infusion of H2 antagonists has
`caused bradycardia and release of histamine, responses
`common to many basic drugs. For recent reviews of the
`pharmacology and adverse effects of H2 antagonists, see
`Deakin and Williams, 1992; and Wormsley, 1993.
`Drug Interactions. All agents that inhibit gastric acid se(cid:173)
`cretion may alter the bioavailability and rate of absorption
`of certain drugs secondary to changes in gastric pH (see
`"Antacids," below, and Chapter 1).
`Cimetidine (but not the other H2 blockers) inhibits the
`activity of cytochrome P450, thereby slowing the metabo(cid:173)
`lism of many drugs that are substrates for hepatic mixed(cid:173)
`function oxidases. Ranitidine, although it interacts weakly
`with cytochrome P450 in vitro, famotidine, and nizatidine
`do not inhibit the hepatic cytochrome P450 system. The
`concurrent administration of cimetidine will prolong the
`half-life of a host of drugs, including phenytoin, theo(cid:173)
`phylline, phenobarbital, cyclosporine, benzodiazepines not
`metabolized by glucuronidation, carbamazepine, propra(cid:173)
`nolol, Ca2+ channel blockers, quinidine, mexiletine, sul(cid:173)
`fonylureas, warfarin and tricyclic antidepressants such as
`imipramine. Cimetidine can inhibit tubular secretion of
`procainamide, increasing the plasma concentration of the
`drug and its cardioactive metabolite, N-acetylprocainamide.
`Such interactions may require either reduction of dosage
`or alteration of the regimen. There are reports that H2 an(cid:173)
`tagonists inhibit gastric mucosal ethanol metabolism and
`thereby elevate blood alcohol levels. Such effects are vari(cid:173)
`able and controversial and, in any event, are not likely to
`be clinically relevant. The drug interactions of H2 antago(cid:173)
`nists have been reviewed by Hansten (1994).
`
`Therapeutic Uses. The clinical use of H2 recepto . .
`1 ·'~1-
`tagonlsts stems from their capacity to inhjbit gastric
`secreti n , e. pec ially in patients with peptic ulccratio ac,ct
`appr priate doses, lhe various H2 antagonists appear ton. 111
`.
`I
`h
`.
`Pro,
`u
`d
`uce equ1va ent t erapeuLtc responses. o 2 receptor ant
`on.L~t!l arc available for both oral and parenteral adlllin~~­
`tration. Cimeridine (TAGAMRT) ami ranitidine ranltr'd·ts-
`.
`.
`. .
`·lire
`hydrocholonde. ZANTA ) are avatlable a, tablets ant.! Us .
`liqu id; niz.atidine AXm) is available as capsules; !amor ~
`dine (rrrr ro) is av~tilable as tablets, us an oral suspensio '
`and as a solution for intravenous injection. These drugs cu~·
`we ll tolerated a~ dos s considerably in excess of those re~
`quired to pr duce substantial .inhibition of ga tric acid e(cid:173)
`cretiou. Consequently, despite their short ha lf-live.c;
`in
`p.lasma. H2 receptor antagoni ts can be admiu i. tered in rel(cid:173)
`atively l1.1rge quantities once or twice da ily to provide ef.
`fective therapy. Once- laily admini. tra[ iOn of H2 receptor
`antagoni ts i. most effective when the dose is administered
`before s leep, so that lhe agents are at their highest con(cid:173)
`centration when Lhey are a ting to block nocturnal ga tric
`acid secreti()ll. In patients with active peptic ulcer di ·ease
`who are infected with H. pylori, therapy to eradicate the
`bacterium see below) should be given concurrenUy to help
`promote healing and prevent 1·ecurrence.
`
`Duodenal Ulce1: H1 nnwgonists profoundly lower basal and noc(cid:173)
`turnal s~cretion of ttcid and thnt stimu lated by meals 1tnd other fac(cid:173)
`tors: they reduce boU1 the pu.in of duodenal ulcer and lhe consump(cid:173)
`tion of tmtaclds, and ll1cy hasten heallng. For the treatment of active
`duodenal and benign gastric ulcers, a large do e before bedtime
`(cimetidine, 800 mg; ranltidioe, 300 mg: niztuidlne. 300 mg; fumo(cid:173)
`tidine, 40 mg) or ha lf the dose twice unity is an eCfective regimen.
`Duodenal ttlccr~ IJStm lly heal with 4 to H weeks of treat111ent. Fol(cid:173)
`lowing healing, a maintenance dose (half the dru ly treatment dose)
`can redvce the ll kcilbood of recurrent diseuse. About 10% of patienL\
`do not respond in this period. and more prolonged tremmem with H2
`antagonists is then of questionable value. After , ucccs~u1 treatment,
`ulcer recur within a yew· in about 50% of patients; ll1ls rate can be
`reduced to about 20'il by the administration of u maintenance dose
`of au H2 ant11gonist once t.laily nt bedtime. Eradication of H. pylori
`rcduc.:s the rate of relapse in infected patients.
`Gastric Ufcer. H 2 amagonists nl o accelerate the beating of benign
`gnstric Ltlccr-;; treatment fo.r 8 weeks is sufficient fot 50 to 75% of
`patients. A more prolonged treatment, up to 16 weeks, produces a
`higher rate of healing. The drugs also markedly reduce the rate of
`relapse when given in maintenance doses at bedtime. Eradication of
`H. pylori should be undertaken in infected patients to reduce the rate
`of recurrent ulcers.
`ln rhis tli •en e, 11 non-bcta-celltumor
`Zollirtgllr·Ellison S)'ndrome.
`of the puncreatic i slel~ muy produce gastrin in a quanlily ~umcient
`to ~timulat e secretlun of ga~u·i c acid to Hfc-threatening levels. A!(cid:173)
`though H2 receptor u.magon!sts in high doses may be benelicial, they
`du not niw<tyl> produce adequate supp.ra~sion of this ga.slrin-. tlmu(cid:173)
`lntcd ncid secretion (~'('(' Figure 37- 1). rnhibitors of the H I ,K 1
`ATPnsc nre the ther~py of choice for this cpndiLion (see he! w).
`Gastmeso[JIIftgeal Reflux Di.fease. A mnjor llsc of H2 receptor an
`lllgonists is fo r the chronic 111nnagemcnt of gastmc.~ophagc:ll n:flll ~
`
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`
`

`
`-
`
`A «OCH2~~:
`
`N
`dy 5~o
`\W)-NH
`
`LANSOPRAZOLE
`
`OOH3
`OMEPRAZOLE
`
`SULFENIC ACID
`OCH3
`CH30 (CH3
`
`S -OH
`
`'~~ J
`NA NH Q OCH3
`
`OCH .•
`
`CH,« H,
`A S - S-Enzyme
`N ~ NH Q OCH3
`
`ENZYME-INHIBITOR COMPLEX
`Figure 37-5. Inhibitors of the gastric H+,K+ -ATPase.
`
`A. Structures of lansoprazole and omeprazole. B. Mecha(cid:173)
`nism of irreversible inhibition of H+ ,K+ -ATPase by pump
`inhibitors. In the acidic environment of the parietal cell
`canaliculi, these "pro-drugs" are converted to sulfenamides
`that interact covalently with sulfhydryl groups in the ex(cid:173)
`tracellular (luminal) domain of the proton pump.
`
`sulfenamide within the acidic canaliculi and adjacent to the
`target enzyme. Administration of omeprazole (Figure
`37-5, B) results in permanent inhibition of enzyme activ(cid:173)
`ity in vivo; secretion of acid resumes only after insertion
`of new molecules of H+ ,K+ -ATPase into the luminal mem(cid:173)
`brane (see Lindberg et al., 1990; McTavish et al., 1991).
`
`fl llfl il~n'ORS OF H 1 ,K 1 -ATPase
`
`The ultimate mediator of acid secretion is the H+ ,K+(cid:173)
`ATPase ("proton pump") of the apical membrane of the
`parietal cell (see Figure 37-1 ). Since this pump is unique
`to parietal cells, a number of specific inhibitors of it have
`been developed; a family of substituted benzimidazoles
`were discovered first, and two of these compounds, lanso(cid:173)
`prazole and omeprazole (Figure 37-5, A), have been released
`for clinical use in the United States (see Lindberg et al.,
`1990; McTavish et al., 1991; and Barradell et al., 1992).
`These agents offer a means to inhibit acid secretion to any
`desired level. They are especially useful in patients with
`hypergastrinemia and may be valuable in those whose pep(cid:173)
`tic ulcer disease is not well controlled by H2 antagonists.
`Proton pump inhibitors contain a sulfinyl group in a
`bridge between substituted benzimidazole and pyridine
`rings (see Figure 37-5, A). At neutral pH, omeprazole and
`lansoprazole are chemically stable, lipid-soluble, weak
`bases that are devoid of inhibitory activity. These neutral
`weak bases reach parietal cells from the blood and diffuse
`into the secretory canaliculi, where the drugs become pro(cid:173)
`tonated and thereby trapped. The protonated agent re(cid:173)
`arranges to form a sulfenic acid and a sulfenamide. The
`su.I~enamide interacts covalently with sulfhydryl groups at
`cntical sites in the extracellular (luminal) domain of the
`nmrubi··m • p::urnin J[ + ,.K + · ATPuse (Fi ur
`7- 5 E .
`'(;UI. · wi h . ...,.
`f inhi ht r
`h ul irthl ition
`m pral·ol anu ]ali.S }
`un P mol •cule
`rrazl ~~ must hils
`c nsidered as pr drugs "Uut need t
`. peciH ity
`f 111
`Je " 'llvme