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Clinical Use of Drugs

:
Pharmacotherapy GI Disorders
Upper GI Disorders
GI Anatomic region
Gastric Acid Secretion

Neuronal

sight, smell, taste → cholinergic pathway

Physical

strecth → ↑acetylcholine & ↑gastrin

Hormonal

timulate parietal cells to secrete gastric
acid

Gastrin

!cetylcholine

Histamine
Proton pump "H
#
$%
#
& !'Pase(
!cid ecretion
Physiological & Pharmacological Gastric !cid ecretion
Pharmacotherapy of
Acid – Related Disorders
Acid-suppressing drugs
Proton-pump Inhibitors (PPIs)
Proton-pump Inhibitors (PPIs)

)i*e PPIs a*aila+le in clinical use : Omeprazole,
Esomeprazole, Lansoprazole, Rabeprazole, &
Pantoprazole

Similar in their pharmacological properties

!ll PPIs ha*e e,ui*alent efficacy at compara+le
doses

PPIs diminish daily production of acid +y -. /
012 →
most potent gastric suppressors
most potent gastric suppressors

PPIs →
prodrugs
prodrugs, re,uire acti*ation in acid
en*ironment → tetracyclic sulfenamide → una+le
to diffuse +ac3 to canalicular mem+rane

!cti*ated form of PPIs covalently bound to
H
#
$%
#
&!'Pase → !cid secretion resume after
newly formed H
#
$%
#
&!'Pase molecules →
Prolong acid suppression "45 / 5- hours(

PPIs +loc3 final steps of acid secretion
PPIs +loc3 final steps of acid secretion

Effective in acid suppression regardless of other
stimulating factors

Dosage form : Enteric – coated drugs, enteric – coated
granules, enteric – coated tablets, podered in combination
ith bicarbonate → to pre*ent degradation +y acid in the
stomach
Pharmaco3inetics :

6apidly a+sor+ed, highly protein / +ound,
e7tensi*ely meta+oli8ed +y hepatic C9Ps

C9P4C:0 & C9P;!5

C9P4C:0 genotype

!sian *s Caucasian or !frican !merican (!" #s (!" #s
!") !")

Chronic renal failure does not lead to
accumulation of PPIs with once&a&day dosing

Hepatic impairment su+stantially reduce
clearence of esomepra8ole and lansopra8ole

<ost common : nausea, a+dominal pain,
flatulence, & diarrhea

u+acute myopathy, arthralgia, headache, & rash

Inhi+ition of C9P4C:0, slower the clearence of
phenytoin, disulfiram, & other drugs meta+oli8ed
the same en8ymes(

Increase e7pression of C9P:!4 "increase
clearence of imipramine, antipsychotic drugs,
tacrin, & theophylline(

=oss of gastric acidity → affect +ioa*aila+ility of
3etocona8ole, ampicillin esters, & iron salts

!hronic use ≈ hip fracture, possi+ly decreasing
Ca
4#
a+sorption
Ad#erse $ffects % Dru& Interactions

<ost common : nausea, a+dominal pain,
flatulence, & diarrhea

u+acute myopathy, arthralgia, headache, & rash

Inhi+ition of C9P4C:0, slower the clearence of
phenytoin, disulfiram, & other drugs meta+oli8ed
the same en8ymes(

Increase e7pression of C9P:!4 "increase
clearence of imipramine, antipsychotic drugs,
tacrin, & theophylline(

=oss of gastric acidity → affect +ioa*aila+ility of
3etocona8ole, ampicillin esters, & iron salts

!hronic use ≈ hip fracture, possi+ly decreasing
Ca
4#
a+sorption
Ad#erse $ffects % Dru& Interactions
'herapeutic Use

Promote healing of gastric & duodenal
ulcers

Gastroesophageal reflu7 disease "G>6D(

Hypersecretory conditions : ?olinger&
>llison syndrome

Pre*ention of recurrence of N!ID /
associated gastric ulcers
(

Receptor Anta&onists

H46!s → competiti*e inhi+itors of H4
receptor on +asolateral mem+rane of parietal
cells

!*aila+le drugs : !imetidine, Ranitidine,
"amotidine, #izatidine

Differ in pharmaco3inetics & propensity to cause
drug interations

H46!s predominantly inhi+it +asal acid
secretion → suppressing nocturnal acid
secretion

Pharmaco)inetics

6apidly a+sor+ed, pea3 serum concentration
achie*ed within : / ; hours

mall percentage of H46!s are protein&+ound

=i*er disease per se is not indication for dose
ad@ustment

>7creted +y 3idneys through filtration & tu+ular
secretion → reduce dose on patients with
reduced creatinine clearence
Ad#erse $ffects % Interactions

H46!s generally well&tolerated

=ow incidence of !>s : diarrhea, headache, fatigue, muscular
pain, & constipation

Neurologic : headache, di88iness, drowsiness, lethargy,
hallucination, psychosis(

=ong&term use :

Cimetidine at high doses → inhi+it testosterone +inding to
androgen receptors & inhi+ition of C9P reduce
hydro7ylation of estradiol

$alactorrhea in omen, and gynecomastia, reduced $alactorrhea in omen, and gynecomastia, reduced
sperm counts & impotence in men sperm counts & impotence in men

Alood dyscrasia including throm+ocytopenia
ha*e +een reported

H46!s cross the placenta & e7creted in +reast
mil3
'herapeutic Uses

Promote healing of gastric & duodenal ulcers

'reat uncomplicated G>6D

Pre*ent occurrence of stress ulcers
A&ents that $nhance *ucosal Defences
Prostaglandin !nalog : <isoprostol

ynthetic analog of PG>:

Gastric acid secretion inhi+ition / Dose related

:.. / 4.. ug significantly inhi+it +asal secretion " up to 012(
or food / stimulated secretion " -12 inhi+ition(

Cytoprotecti*e role of prostaglandin toward gastric
acidity

timulate Gi pathway → decreasing c!<P & gastric acid
secretion

timulate mucin & +icar+onate secretion

Increase +lood flow

6ecommended dose for ulcer prophyla7is : 4.. ug
four times a day

)re,uent dosing limited its use → incon*enience


<isoprostol can cause e7acer+ation of
inflammatory +owel disease

Contraindicated in pregnancy → increase uterine
contractility
'herapeutic Use

'o pre*ent N!ID&induced mucosal in@ury
Sucralfate

ulfated polysaccaride → Bctasulfate of sucrose

%nhibit pepsin&mediated hydrolisis of mucosal proteins
contri+utes to mucosal erosion & ulceration

In acid en*ironment "pHC5(, sucralfate → cross&lin3ing →
*iscous & stic3y polymer that adhere to epithelial cells &
ulcer crater up to D hours after single dose

timulating secretion of PGs & growth factors
'herapeutic Use

In critically patients, sucralfate may offer ad*antage
o*er PPIs & H46!s in pre*enting stress ulcers

Condition associated with mucosal inflammation $
ulceration which is not responsi*e to acid suppression
such as oral mucositis "radiation & aphtous ulcer(, +ile
reflu7 gastropathy
+ismuth Salts

Ainding to and protecting mucosal lesion

>nhancing cellular protecti*e mechanims

!ntimicro+ial effects, primarily againts
'(pylori

)re,uently use in com+ination with other
anti+iotics to eradicate '(pylori
Pro)inetic a&ents
Pro)inetic a&ents
<etoclopramide & Aetanechol

timulate motility of upper GI & increase =>
"lower esophageal sphincter(

Patients with delayed gastric emptying or refractory to
other a*aila+le treatment options
General Guidelines of medical management of Gastroesophageal
Reflux Disease (GERD)
Meta-analysis of H2-receptor
Meta-analysis of H2-receptor
antagonists on Functional (Non-Ulcer)
antagonists on Functional (Non-Ulcer)
Dyspepsia
Dyspepsia
Meta-analysis of H2-receptor
Meta-analysis of H2-receptor
antagonists on Functional (Non-Ulcer)
antagonists on Functional (Non-Ulcer)
Dyspepsia
Dyspepsia
Comparison of Prokinetic, ci! "uppression,
Comparison of Prokinetic, ci! "uppression,
an! ntian#iety $%erapies in Functional
an! ntian#iety $%erapies in Functional
Dyspepsia
Dyspepsia
Both Mosapride and Famotidine significantly improved the
symptoms of Functional Dyspepsia within 2 weeks and the
improvement was maintained for 8 weeks after the beginning of the
study (p < !"#
Metaanal!sis " #elico$acter p!lori eradication impro%e s!mptoms in nonulcer
d!spepsia &
''Is %s A#( " Effect on persistent or re$leeding of peptic ulcer
$n patients with peptic ulcer and %! pylori infection& prolonging $n patients with peptic ulcer and %! pylori infection& prolonging
therapy with proton pump inhibitor after a triple therapy for ' therapy with proton pump inhibitor after a triple therapy for '
days with a proton pump inhibitor and two antibiotics is not days with a proton pump inhibitor and two antibiotics is not
necessary to induce ulcer healing necessary to induce ulcer healing
Step-Up #s Step-Do,n 'herapy
in -e,-.nset Dyspepsia

)ouble&blind, randomized controlled trial

tep&up therapy : started with antacids, switched to
H4&receptor antagonists, and then ended with proton
pump inhi+itors "PPIs(

tep&Down therapy : re*ersed order

(tep)*p therapy somewhat more (tep)*p therapy somewhat more cost effective cost effective than a than a
step)down approach& but effectiveness of treatment step)down approach& but effectiveness of treatment
and adverse events are similar! and adverse events are similar!
-ausea % /omitin&
Patophysiology of >mesis

Nausea, the imminent need to *omit

!ssociated with gastric stasis

6etching,

=a+ored mo*ement of thoracic & a+dominal muscles +efore
*omiting

Eomit

)orceful of GI contents caused +y GI retroperistalsis

!ct of *omiting re,uire coordinated contraction of a+dominal
muscles, pylorus, antrum, raised gastric cardia, diminished
lower esophageal sphincter, & esophageal dilatation

Chemoreceptor trigger 8one "C'?(

Neurotransmitter receptor : cholinergic, histaminic,
serotonergic, dopaminergic, opiate, neuro3inin, &
+en8odia8epin receptors
Specific etiolo&ies of -ausea % /omitin&
$meto&enicity of 0hemoterapeutic A&ents
$meto&enicity of 0hemoterapeutic A&ents
Presentation of -ausea % /omitin&
'reatment
Non pharmacologic

Dietary restriction if appropiate

ta+le physical position

Psychological & +eha*ioral inter*ention

6ela7ation

Aio&feed+ac3

elf&hypnosis

Cogniti*e distraction

Guided imagery

ystematic desenti8ation

>tc
Pharmacological inter*ention
Pharmacolo&ical Inter#ention
)actors that ena+le clinician to discriminate the
choices of antiemetic must +e recogni8ed, :

'he suspected etiology of symptoms

)re,uency, duration, & se*erity of the episodes

'he a+ility of patients to use oral, rectal,
in@ecta+le or transdermal medication

'he success of pre*ious antiemetic medication
1a2ati#e3 0athartics3 % 'herapy of 0onstipation

)luid content is principal determinant of stool
content "F. / -12 contain water(

- / 0 = of fluid enter small intestine & : / :G1 =
crossing ileocaecal *al*e, colon e7tracts most of
remaining fluid & ' :.. ml of fecal water daily

ecretory changes, +owel mo*ement, transit time,
e7tent of a+sorption determine the consistency of
stool

Neurohormonal mechanisms, pathogens, drugs might alter
processes a+o*e

Up to D.2 of patients with constipation ha*e normal
colonic transit

Predominant factors underlying constipation often not
o+*ious & therapy remain empiric & non specific

=a7ation : e*acuation of formed fecal material
from rectum(

Catharsis : e*acuation of unformed, usually
watery fecal material from the entire colon

*he terms fre+uently used interchangebly

,ode of -ction of La.ative /

>nhancing retention of intraluminal fluid +y
hydrophilic or osmotic mechanims

Decreasing the net a+sorption of fluid +y effects on
small& and large&+owel fluid & electrolyte transport

!ltering motility +y either inhi+iting segmenting
"nonpropulsi*e( contractions or stimulating
propulsi*e contractions
Antidiarrheal a&ents

Bral rehydration solution is the cornerstone of
therapy for patient with acute illness resulting
significant diarrhea

Pharmacotherapy should +e reser*ed for patients
with persistence symptoms

Selected Antidiarrheal Agents Selected Antidiarrheal Agents