pharmacotherapy of gi disorders

7/23/2019 Pharmacotherapy of GI Disorders

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PHARMACOTHERAPY OF GASTROINTESTINAL DISORDERS

Joseph Heitman

I. Ulcers

-Gastric physiology -History and revolution in thought

-Treatment strategies

A) histamine H2receptor antagonists

B) H+pump antagonists

) prostaglandin antagonists

!) sur"ace agents and antacids

#) eradication o"Helicobacter pylori$ith %ismuth and anti%iotics

II. &ther 'dia%etic gastroparesis( re"lu esophagitis( gastric stasis( anoreia nervosa)

III. *ausea and vomiting -physiology

-treatment

I. !iarrhea

. onstipation

I. In"lammatory %o$el disease

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Gastric Phsio!o"

The stomach is an outpocet o" the gastrointestinal tract in $hich ingested "ood undergoes

mechanical and chemical changes that promote a%sorption in the small and large intestine. The gastric

mucosa contains specialied structures( no$n as oyntic glands or gastric pits '$hich mae up the

"undus and corpus). This specialied mucosa produces acid 'Hl) '"rom parietal cells)/ the proteolyticenyme pepsin '"rom chie" cells)/ mucous '"rom mucous cells)( and hormones '"rom endocrine cells).

Acid is not a%solutely re0uired "or digestion %ecause individuals $ith achlorhydria usually can digest

"ood $ithout mala%sorption.

Acid does serve to1,. solu%ilie "ood

2. activate pepsinogen to pepsin

. disin"ect3. stimulate chemoreceptors on endocrine cells in the duodenum to promote release o" the hormones1

-gastric inhi%itory peptide 'GI4) increases activity o" gastric smooth muscle and glands

-cholecystoinin '5) - stimulates contraction o" gall %ladder and release o" %ile

-secretin - stimulates pancreatic secretion

4epsin( together $ith chymotrypsin in the duodenum( digests proteins to peptides. These peptides

play a regulatory role and( %y %inding to receptors in the stomach( increase hormonal and neural input and

gastric motility.

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6astly( mucous 'neutral "luid containing glycoproteins) protects the gastric mucosa "rom %oth

mechanical and chemical damage.


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#!cers $ the Historica! %ie& an' Recent Re(o!)tion in Thin*in"

Ulcers are lesions o" the gastroduodenal mucosa etending through the muscularis mucosa. They

a""ect 7-,89 o" the population( and as many as 78-:89 recur. In the case o" gastric ulcers( roughly 79

are malignant and thus one needs to demonstrate healing has occurred "ollo$ing treatment.

The historical vie$ o" ulcers $as that there $as a %alance o" po$ers in the gastric mucosa

%et$een acid production and mucosal de"enses and that ulcers resulted "rom su%tle shi"ts in this %alance.There is little evidence o" increased acid production in gastric ulcer and only in a minority o" duodenal

ulcers. It is true( ho$ever( that acid is re0uired "or ulcer "ormation( and hence %locing acid production

pharmacologically can hasten ulcer healing.

The net models "or ulcer "ormation $ere that several "actors contri%uted to alter acid production(

to decrease mucosal de"ense( or %oth. These "actors $ere thought to include smoing( alcohol( stress(diet( and treatment $ith aspirin and other *;AI!s. Therapies included alterations in li"estyle to reduce

smoing( drining and stress and to introduce %lander diets.


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receptors) and parietal cells '@receptors) to produce histamine and acid( respectively. This is the %asis

"or the surgical management o" ulcer %y vagotomy or partial vagotomy. Histamine released %y endocrine

cells %inds to parietal cell H2histamine receptors and stimulates acid production. &ther local paracrine

"actors include prostaglandins( $hich inhi%it acid production. 6astly( gastric endocrine cells release

gastrin into the circulation in response to stretch and chemoreceptors. Gastrin returns to the stomach toact on endocrine cells and increase histamine release( and on parietal cells directly to increase acid

production %y histamine. &ther endocrine cells secrete somatostatin( $hich counteracts the stimulatorye""ects o" gastrin.

In the parietal cell( histamine and prostaglandins act via G-proteins to increase or decrease(

respectively( cA@4 production %y adenylate cyclase. In contrast( gastrin and acetylcholine increase a2+

concentrations. Activation o" these t$o distinct signalling path$ays underlies the phenomenon that1 ,)

prostaglandins inhi%it histamine action( %ut not isolated acetylcholine or gastrin signals( 2) gastrin and

acetylcholine potentiate histamine action '%y acting on 2 di""erent signals). The second messengers

cA@4 and a2+activate protein inases. The net step in regulating acid production is not clear. H+

secretion re0uires not only the H+=5+echange pump( %ut also a 5+=l-cotransporter that allo$s 5+ions

to enter tu%ulovesicles and canaliculi and then echange "or H+ entry. ;ome evidence suggests that

insertion o" the 5+carrier into the mem%rane is the regulated step.

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#!cer Treatment Strate"ies

Histamine H2Receptor Anta"onists

Histamine plays a central critical role in acid production %y parietal cells. Thin o" histamine as

the central signal and the others as accessory signals that inhi%it '4Gs) or potentiate 'acetylcholine(

gastrin) histamine action. Histamine H2receptor antagonists %loc acid production in response to "ood(

gastrin( or vagal input.*inety percent o" ulcers are treated $ith histamine H2receptor antagonists( $hich are derivatives

o" histamine in $hich the ethylamine side chain is replaced $ith %uly derivatives. In some cases the

imidaole ring is su%stituted %y a "uran 'ranitidine) or thiaole '"amotidine( niatidine) ring. Doughly 3.3

%illion dollars is spent on histamine H2receptor antagonists in the U.;. alone. The most commonly used

histamine H2 receptor antagonists are cimeti'ine 'Tagamet) and raniti'ine '>antac). These agents

competitively inhi%it the histamine-receptor interaction and decrease acid and pepsin production. These

drugs are rapidly and $ell a%sor%ed( have pea levels at ,-2 hr( and have short hal"-lives. Because they

are $ell tolerated( they can %e given in larger doses only once or t$ice per day( despite their short hal"-

li"e. Both are ecreted %y the idney $ith little or no meta%olism. High-dose( long-term cimetidine 'and

not other histamine H2 receptor antagonists) is associated $ith reversi%le impotence( decreased li%ido( andgynecomastia 'secondary to prolactin secretion( androgen receptor %inding( and inhi%ition o" estradiol

meta%olism %y cytochrome 4-378). imetidine alone inhi%its cytochrome 4-378 activity. Dare sidee""ects1 mental status changes in elderly $ith renal or hepatic dys"unction( leuopenia. Danitidine has

%een associated $ith reversi%le drug-induced hepatitis.


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H3P)mp Inhi+itors

Acid is ultimately secreted "rom the apical sur"ace o" parietal cells %y the H +-5+echange pump.

;everal %enimadaole derivatives inhi%it this pump. Omepra4o!e and a "e$ other H+pump %locers are

used clinically. &mepraole is an etremely potent inhi%itor o" gastric acid secretion and is there"ore

invalua%le in treating ulcers resistant to histamine H 2receptor antagonist therapy and ulcers that result

"rom >ollinger-#llison syndrome. >D results "rom non-%eta cell islet tumors o" the pancreas orduodenum $hich secrete gastrin and overstimulate acid production( resulting in ulcers.

&mepraoleEs mechanism o" action is unusual. The compound is sta%le and does not inhi%it the

pump at neutral pH. At acidic pH '%elo$ 7) in the lumen o" parietal cell canaliculi( omepraole %ecomes

protonated and rearranges to t$o active species that covalently react $ith the H+ pump( irreversi%ly

inactivating it. &mepraole speci"ically accumulates in the canalicular lumen $hen the pH is %elo$ 7(%ecause the protonated species are changed and donEt escape the vesicles. As the pump is %loced( pH

rises and( $hen it reaches 7( omepraole stops accumulating in the canaliculi.

&mepraole can reduce acid production %y :79 or more. This results in increased gastrin

production( $hich can cause mucous cells to proli"erate( even to the point o" carcinoid tumors( in animals.

There is as yet no evidence o" this in humans. Ho$ever( carcinoid tumors are no$n to occur in patients

$ith gastrinoma or chronic atrophic gastritis.

&mepraole is characteried %y oral administration( rapid a%sorption( %inding to plasma protein(

hepatic meta%olism( short hal"-li"e '8-:8 min)( renal ecretion. The drug is $ell tolerated( even $hen


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given to ># patients in high dose "or long periods. Three percent incidence o" GI distur%ance( rarer *;

e""ects 'headache( diiness).

Prosta"!an'ins

4rostaglandins inhi%it histamine stimulation o" parietal cells and also protect the mucosa %yenhancing %lood "lo$ and mucous secretions. *on-steroidal antiin"lammatory drugs '*;AI!s) promote

ulcers %y decreasing prostaglandin levels. In some cases( patients on chronic *;AI! theapy receive

concomitant treatment $ith the 4G#, analog( misoprosto!. @isoprostol is also e""ective in duodenal

ulcer( %ut o""ers no advantage over other therapies. Given orally( side e""ects include diarrhea( cramping(and potentially a%ortion. There"ore it sho)!' not +e "i(en to pre"nant or potentia!! pre"nant &omen.

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Antaci's an' S)r,ace A"ents

Antacids have %een used in various "orms "or centuries to treat esophageal re"lu( gastritis and

ulcers. Although more e""ective agents are availa%le "or ulcers( antacids are still important and simpleadFuvant therapies that 0uicly provide symptomatic relie". onsiderations are %u""ering capacity( sodium

content( and side e""ects 'diarrhea( constipation).

Typical agents 'see ta%le) include magnesium hydroide @g'&H)2( $hich is a potent antacid %ut

can cause an osmotic diarrhea. or this reason it is usually com%ined $ith aluminum hydroide Al'&H) $hich( although less potent( has a counteracting constipating e""ect. 'To remem%er this( thin o" the name

@aalo magnesium + aluminum + oide in $hich magnesium comes "irst %ecause it is more potent and

causes diarrhea).

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S)cra!,ate

This is a local coating agent 'comple o" sucrose octasul"ate and polyaluminum hydroide) that

acts locally on the mucosal sur"ace and is highly e""ective in treating ulcers. It is most e""ective given

prior to( rather than a"ter( meals. At pHs %elo$ 3 'i.e.( in the stomach) sucral"ate polymeries to a highlyviscous gel. ou can thin o" this as something lie super-mucous that "orms $here it is needed.

;ucral"ate causes constipation in a%out ,89 o" patients. It is very commonly used in hospitaliedpatients.

Helicobacter pylori- Anti+iotics an' Pepto$5ismo! ,or #!cers

Helicobacter pylori is a spiral gram negative microaerophilic 'lies lo$ amounts o" oygen)

%acillus( "irst seen in gastric tissue in ,:2( "irst cultured "rom gastric %iopsies in ,:2( that is specially

adapted to survive in the stomach and duodenum 'see 4eterson( *#?@ 231,83-,83( ,::,).

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H. pyloriproduces a hyperactive "orm o" the enyme urease( $hich catalyes conversion o" urea

to ammonia and &2and allo$s the %acterium to partially neutralie the acidity o" the stomach. This is

the %asis o" a simple color assay "or the %acterium in $hich urease in %iopsy specimens is detected %y a

pH-dependent color change. In random populations( prevalence is ,89 "or those under 8 years %ut rises

to C89 "or those over C8 years. 4revalence is ,889 in patients $ith duodenal ulcers and 89 in patients$ith gastric ulcers. That many individuals in"ected $ith H. pylorido not develop ulcers suggests other

"actors contri%ute to ulcer development.The transmission route is not no$n. The "ecal-oral route has %een proposed( %ut the %acterium

has not %een "ound in stool. 4erson-to-person transmission is possi%le( %ecause the %acterium is not

"ound in "ood( $ater( or animals $ith "re0uent human contact 'pets( livestoc). Gastroenterologists have

t$ice the average prevalence. H. pylori is associated $ith histological changes o" the gastric mucosa

'gastritis( in"lammation). The central 0uestion is $hether the %acterium causes these changes or simply

lives there a"ter the "act. In t$o human su%Fects $ho s$allo$ed H. pylori cultures( %oth su""ered

in"lammation o" the gastric mucosa. &ne spontaneously resolved( the other developed chronic gastritis.

In addition to histological changes( H. pylori in"ection is associated $ith increased gastrin and

acid secretion.

Decent studies reveal that anti%iotic treatment com%ined $ith more standard ulcer medication(

such as ranitidine( is highly e""ective and reduces relapse. or eample( patients treated $ith a t$o-$ee

course o" ranitidine( tetracc!ine( metroni'a4o!e'anti%iotic selective "or anaero%ic and microaerophilic%acteria and anoic cells( undergoes reduction and then damages !*A) and +ism)th s)+sa!ic!ate

'4epto-Bismol) had only ,29 relapse( compared to a 39 'gastric) and :79 'duodenal) relapse rate "or

ranitidine treatment alone. Institution o" anti%acterial treatment "or ulcer could largely eliminate the need

to treat relapses and vastly reduce the overall cost o" ulcer treatment. Because H. pyloricauses chronicatrophic gastritis in some patients( it may also play a role in the etiology o" gastric carcinoma. This $ould

%e the "irst association o" %acterial in"ection $ith cancer.

A''itiona! in,ormation onHelicobacter pylori,rom s!i'es

Dia"nosis !iagnostic approaches "orH. pyloriin"ection include1 a%normal histology o" gastric

mucosa( serological tests as signs o" in"ection( a %reath test in $hich ,-la%elled urea 'ingested) is

meta%olied %y the %acteria and released as ,-la%elled &2in the %reath( and "inally a color assay o"%iopsy specimens that detects a urease-dependent pH change.

Treatment &ne no$-standard therapy is 6)a'r)p!e Therap( $hich consists o" tetracycline(

%ismuth su%salicylate( metronidaole and a histamine H2 receptor antagonist 'cimetidine or ranitidine).

Alternatives include1 su%stitution o" tetracycline %y amoicillin( su%stitution o" metronidaole $ith

clarithromycin. Alternatively( some results suggest a dual therapy o" amoicillin plus omepraole 'protonpump inhi%itor that also illsH. pylori) may %e e""ective in some cases.

Association &ith cancer ive lins %et$eenH. pyloriand gastric lymphoma=carcinoma

,. H. pyloripresent in patients $ith gastric lymphoma=carcinoma

2. Date o"H. pyloriin"ection increased in these patients.. Dis o" cancer increased in in"ected vs. non-in"ected individuals

3. H. pyloriin"ection precedes diagnosis o" carcinoma=lymphoma

7. #radication o" H. pyloricaused tumor remission in patients $ith %iopsy-

proven lo$-grade gastric @A6T lymphomas

Mo'e! o, the re!ationship +et&een H. pylori an' "astric !mphoma7carcinoma H. pylori

in"ection leads to chronic gastritis( epithelial cell hyperplasia( and increased ris o" malignant

trans"ormation to gastric carcinoma. 6ymphoid tissue is normally a%sent "rom the stomach. In"ection

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results in accumulation o" lymphoid tissue '@A6T-mucosa associated lymphoid tissue). 6ymphoid

hyperplasia( proli"erating B-cells( and possi%ly dietary eposure to carcinogens leads to a trans"ormation

o" B-cells to lo$-grade @A6T lymphoma. 4rogression "rom lo$- to high-grade lymphoma can then

occur.

Other Gastric Disor'ers

Metoc!oprami'e'structurally related to the anesthetic procainamide)

@etoclopramide is a dopamine antagonist that stimulates gastric motility and emptying and has

an antiemetic activity 'more a%out this to come).!opamine is a neurotransmitter in %oth the central and the peripheral nervous system. ;peci"ic

dopamine receptors are present in the GI tract( $here the role o" dopamine is to inhi%it smooth muscle

"unction. @etoclopramide %locs the inhi%itory e""ect o" dopamine( there%y increasing the activity o" GI

smooth muscle. This proinetic e""ect is clinically use"ul in a num%er o" disorders( including

gastroesophageal re"lu( gastric stasis( dia%etic gastroparesis 'something lie dia%etic peripheral

neuropathy only in this case o" the GI tract)( post-surgical gastroparesis( and possi%ly in anoreia nervosa.

Also used to "acilitate placing GI tu%es and "or small %o$el radiographic series.

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@etoclopramide is $ell a%sor%ed orally andhas a short hal"-li"e '3 hr). @ost '89) is ecreted in

the urine $ithout meta%olism.

Na)sea an' %omitin"

*ausea su%Fectively descri%es gastrointestinal discom"ort that o"ten precedes vomiting. !uring

nausea( gastric tone decreases( peristalsis is diminished( and the tone o" the GI tract increases( hindering

transit and promoting re"lu o" contents. omiting is a re"le that evacuates the gastrointestinal tract in a

variety o" conditions( such as pregnancy( post-general anesthesia( drining( and "ollo$ing chemotherapy(

in"ection 'including "ood poisoning)( and motion sicness.

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The vomit re"le loop %egins $ith receptors in the GI tract( $hich $hen stimulated send a signal

through vagal a""erents to the vomit center or chemoreceptor trigger one located in the medulla in the

area postrema near the "ourth ventricle.

The vomiting center is in the lateral ventricular "ormation. ;everal path$ays provide input( including the

chemoreceptor trigger one 'T>)( the vesti%ular system( cortical regions( and visceral a""erents "rom theGI tract. The %lood-%rain %arrier is not $ell-developed around the area postrema( providing it access to

the circulation. Activation o" the vomit center initiates the vomit re"le( during $hich the glottis closes to

protect the lungs( the cardiac sphincter opens( respiratory and a%dominal muscles contract the stomach(

and a reverse peristaltic $ave eFects the stomach contents.

An array o" di""erent antiemetic agents is no$n.


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mediated %y the nervous system( it should not %e surprising that antiemetics are neurotransmitter

antagonists.

The precise $iring o" the vomit center is not no$n. Based on the action o" antiemetics( it has

%een in"erred that cholinergic and histaminergic neurons lin the vesti%ular apparatus to the vomit center(

$hereas dopaminergic neurons act centrally and peripherally during vomiting.

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The antimuscarinic scopo!amineis one o" the most potent agents "or motion sicness and is also

used in vertigo and to reduce postoperative nausea and vomiting. ;copolamine acts centrally to %loc the

vomit center %y inhi%iting acetylcholine actions. ;copolamine is a relative o" atropine and shares similar

side a""ects 'dry mouth( %lurry vision( urinary retention)( %ut crosses the %lood-%rain %arrier more

e""ectively. Typically delivered %y a transdermal patch %ehind the ear( $hich should %e placed prior to theonset o" nausea. @ost "re0uent side e""ects are dry mouth and dro$siness. Advise patients to $ash their

hands a"ter applying the patch to avoid contact o" the drug $ith the eyes.

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The second class o" centrally acting antiemetics is the H, histamine receptor antagonists. These

include 'imenh'rinate '!ramamine)( 'iphenh'ramine'Benadryl)( and mec!i4ine'Antivert). These

agents are use"ul "or motion sicness( vertigo( and 'in etreme cases) pregnancy. Importantly( they are

not use"ul "or nausea associated $ith chemotherapy. In some cases( mecliine is e""ective "or radiation-

associated nausea and vomiting. The most common side e""ect( sometimes use"ul clinically( isdro$siness.

The third class o" centrally or centrally=peripherally acting antiemetics is the dopamine

antagonists( eempli"ied %y proch!orpera4ine'ompaine) and metoc!oprami'e'Deglan)( $hich $as

introduced earlier.

4rochlorperaine is e""ective against postoperative( radiation( and mild chemotherapy associated

nausea and vomiting. It is not active against vertigo or motion sicness( is less e""ective against highly

emetic chemotherapy and can cause etrapyramidal side e""ects.

@etoclopramide is an antiemetic dopamine antagonist that acts centrally and peripherally. In the

periphery( metoclopramide %locs the inhi%itory action o" dopamine and there%y increases smooth muscle

activity and speeds transit time. It is use"ul in treating nausea and vomiting during cancer chemotherapy.

;ide e""ects include1 dro$siness( diarrhea and constipation( restlessness( etrapyramidal reactions 'more

common in children and elderly) including parinsonism( dystonic movements( and tardive dysinesia.

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The last class o" antiemetic agent is the serotonin antagonist

on'ansetron'>o"ran). &ndansetron selectively %locs serotonin 7-

HT receptors( $hich are no$n to %e located on vagal nerve

terminals and in the area postrema. Thus ondansetron may act %oth

peripherally and centrally "or some types o" nausea.

&ndansetron is remara%ly e""ective at preventing nausea

and vomiting "ollo$ing chemotherapy( especially $ith agents such

as cisplatin. &ndansetron is much more e""ective than

metoclopramide "ollo$ing cisplatin.


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&ndansetron is typically given I

%ut is also orally active( hal"-li"e is 3 hr(

:79 is meta%olied %y hydroylation o"

the indole ring and then glucuronide or

sul"ate conFugation. ;ide e""ects includeconstipation( mild elevations in liver

enymes 'A;T=A6T)( and headache.

Diarrhea an' Constipation

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The small intestine and colon are gigantic a%sorptive sur"aces. &n average( : liters o" "luid enters

the small intestine every day 'the vast maFority "rom secretions). &nly ,-,.7 liters o" this "luid reaches the

colon. Because the small intestine normally operates at 789 a%sorptive capacity and the colon can at

most a%sor% only 3-7 liters=day( temporary loss o" a%sorptive capacity overloads the colon and diarrhea

ensues. *ote1 ou should all %e a$are 'or %e$are) that there is a large and %urgeoning literature a%outelectrolyte transport and ion channels in GI "unction that $e could consider in depth. Ho$ever( since

none o" the antidiarrheal agents or laatives $e $ill consider $or %y taing advantage o" this e0uisite

physiological in"ormation( I have not included this here. ou should no$ ho$ever( that in"ectious

agents cause diarrhea %y ,) secreting toins that inhi%it a%sorption or 2) %y directly illing mucosal cells.

Constipation

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or the most part( constipation is an inconvenience and uncom"orta%le( %ut not li"e threatening.

*onetheless( hospitalied patients are o"ten constipated secondary to changes in environment( immo%ility(

medications( or procedures '%arium sul"ate). In some cases 'recent @I or GI surgery)( one $ould lie the

patient to avoid straining.

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6ucily there are a num%er o" remedies. 6aatives can %e divided into several classes1 ,) %ul

agents '"i%er( such as ps!!i)m in @etamucil)( 2) emollient sur"ace agents that so"ten the stool %yallo$ing $ater and "at entry 'such as 'oc)sate or olace)( ) stimulant cathartics( such as the

phenolphthalein derivative +isaco'!'!ulcola) or etracts o" cascaraor senna';enecot) that stimulate

peristalsis( 3) osmotic cathartics that contain nona%sor%a%le salts or sugars that hold $ater in the %o$el

lumen '@il o" @agnesia)( 7) lavage agents( used "or %o$el preps( contain po!eth!ene "!co!'Golytely).

Diarrhea

The causes o" diarrhea are legion. In"ectious diarrhea is common and ills 7 million people(

mostly children( every year.


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The mainstay o" diarrhea treatment should %e ,) oral or parenteral hydration and electrolyte

%alance( 2) treatment o" the speci"ic underlying disorder( and ) lastly( use o" nonspeci"ic antidiarrhealagents.

In some cases( such as travelling( it is inconvenient to have diarrhea and a temporary nonspeci"ic

treatment is to slo$ GI motility( thus promoting a%sorption( $ith either o" the opioid piperidine analogs

'ipheno8!ate'6omotil) or !operami'e'Imodium).

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In,!ammator 5o&e! Disease

There are other GI maladies $e $onEt have time to consider( %ut one additional topic you $ill

encounter is in"lammatory %o$el disease. IB! includes rohnEs disease and ulcerative colitis( $hich are

liely autoimmune disorders in $hich the gastric mucosa is su%Fect to attac. Thus most treatment

strategies employ antiin"lammatory and immunosuppressive agents 'such as glucocorticoids andsul"asalaine).

S)!,asa!a4ine 'given orally) is converted %y colonic %acteria to sul"apyridine 'inactive( causesside e""ects) and 7-aminosalicyclic acid '7-A;A)( $hich inhi%its the lipoygenase path$ay o" leuotriene

%iosynthesis 'aspirin( acetylsalicyclic acid( inhi%its cyclooygenase). 7-A;A alone can %e given as

mesa!amine( usually given as an enema.

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pharmacotherapy of gi disorders

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