Antiulcer converted

For competitive pharmacy exams

1. :By:
AnkitsharmA
M.Pharma (Pharmacology)
Bhupal Nobles University
Udaipur, Rajasthan

2. PEPTIC ULCER
Pepticulceroccursinthatpartofthegastrointestinaltract
(g.i.t.)whichisexposedtogastricacidandpepsin,i.e.the
stomachandduodenum.
Avarietyofpsychosomatic,humoralandvascular
derangementshavebeenimplicatedandtheimportanceof
Helicobacterpyloriinfectionasacontributortoulcer
formationandrecurrencehasbeenrecognized.
Ingastriculcer,generallyacidsecretionisnormalorlow,
whiledeficientmucosaldefence(mostlyimpairedmucus
andbicarbonatesecretion)playsagreaterrole.Induodenal
ulcer,acidsecretionishighinabouthalfofthepatientsbut
normalintherest.

3. C.Ase.—Carbonic anhydrase; Hist.—Histamine; ACh.—Acetylcholine;
CCK2—Gastrin cholecystokininreceptor;
M.—Muscarinic receptor; N—Nicotinic receptor; H2—Histamine H2 receptor;
EP3—Prostaglandin receptor; ENS—Enteric nervous system; ECL cell—Enterochromaffin-like cell;
GRP—Gastrinreleasing peptide; + Stimulation; –Inhibition.

4. Regulation of gastric acid secretion
TheterminalenzymeH+K+ATPase(protonpump)which
secretesH+ionsintheapicalcanaliculiofparietalcells
canbeactivatedbyhistamine,AChandgastrinactingvia
theirownreceptorslocatedonthebasolateralmembrane
ofthesecells.
H2receptorsactivateH+K+ATPasebygeneratingcAMP,
muscarinicandgastrin/cholecystokinin(CCK2)receptors
appeartofunctionthroughthephospholipaseC→IP3–
DAGpathwaythatmobilizesintracellularCa2+.The
cAMPmediatedprotonpumpactivationalsoinvolves
Ca2+.
Gastrinissecretedfromtheantruminresponsetorisein
antralpH,foodconstituentsandvagallymediated
reflexesinvolvingganglioncellsoftheentericnervous
system(ENS).

5. Drugs for Peptic Ulcer

6. H
2 ANTAGONISTS (Cimetidine)
Four H2 antagonists cimetidine, ranitidine, famotidine
and roxatidineare available in India; many others are
marketed elsewhere.
Cimetidineisadequatelyabsorbedorally,though
bioavailabilityis60–80%duetofirstpasshepatic
metabolism.Absorptionisnotinterferedbypresenceof
foodinstomach.Itcrossesplacentaandreachesmilk,but
penetrationinbrainispoorbecauseofitshydrophilic
nature.
About 2/3 of a dose is excreted unchanged in urine and
bile, the rest as oxidized metabolites. The elimination t½
is 2–3 hr.

7. H
2 ANTAGONISTS (Cimetidine): Interactions
CimetidineinhibitsseveralcytochromeP-450isoenzymes
andreduceshepaticbloodflow.
Itinhibitsthemetabolismofmanydrugssothattheycan
accumulatetotoxiclevels,e.g.theophylline,phenytoin,
carbamazepine, phenobarbitone, sulfonylureas,
metronidazole,warfarin,imipramine,lidocaine,nifedipine,
quinidine.
Metabolismofpropranololanddiazepamisalsoretarded,
butthismaynotbeclinicallysignificant.Antacidsreduce
absorptionofallH2blockers.
Whenusedconcurrentlyagapof2hrshouldbeallowed.
KetoconazoleabsorptionisdecreasedbyH2blockersdueto
reducedgastricacidity.

8. Uses of H
2blockers
Duodenal ulcer
Gastric ulcer
Stress ulcers and gastritis
Zollinger-Ellison syndrome: It is a gastric hypersecretory
state due to a rare tumoursecreting gastrin. H2 blockers in
high doses control hyperacidity and symptoms in many
patients, but PPIs are the drugs of choice. Definitive
treatment is surgical.
Gastroesophagealreflux disease (GERD)
Prophylaxis of aspiration pneumonia
Urticaria

9. PROTON PUMP INHIBITORS : Omeprazole
Itistheprototypememberofsubstitutedbenzimidazoles
whichinhibitthefinalcommonstepingastricacid
secretion.
AllPPIsareadministeredorallyinentericcoated(e.c.)
formtoprotectthemfrommoleculartransformationinthe
acidicgastricjuice.
Oralbioavailabilityofomeprazoleis~50%duetoacid
lability.
BioavailabilityofallPPIsisreducedbyfood;theyshould
betakeninemptystomach,followed1hourlaterbyameal
toactivatetheH+K+ATPaseandmakeitmoresusceptible
tothePPI.

10. PROTON PUMP INHIBITORS : Omeprazole
Interactions Omeprazoleinhibits oxidation of certain
drugs: diazepam, phenytoinand warfarinlevels may be
increased. It interferes with activation of clopidogrelby
inhibiting CYP2C19. Reduced gastric acidity decreases
absorption of ketoconazoleand iron salts. Clarithromycin
inhibits omeprazolemetabolism and increases its plasma
concentration.
Adverse effects PPIs produce minimal adverse effects.
Nausea, loose stools, headache, abdominal pain, muscle
and joint pain, dizziness are complained by 3–5%. Rashes
(1.5% incidence), leucopenia and hepatic dysfunction are
infrequent. On prolonged treatment atrophic gastritis has
been reported occasionally.

11. ANTACIDS
Antacids do not decrease acid production; rather, agents
that raise the antralpH to > 4 evoke reflex gastrinrelease
→more acid is secreted, especially in patients with
hyperacidity and duodenal ulcer; “acid rebound” occurs
and gastric motility is increased.
The potency of an antacid is generally expressed in terms
of its acid neutralizing capacity (ANC), which is defined as
number of mEqof 1N HClthat are brought to pH 3.5 in 15
min (or 60 min in some tests) by a unit dose of the antacid
preparation.

12. ANTACIDS
Systemic Antacids NonsystemicAntacids
SodiumbicarbonateItiswatersoluble,acts
instantaneously,butthedurationofactionis
short.Itisapotentneutralizer(1g→12mEq
HCl),pHmayriseabove7.
However,ithasseveraldemerits:
(a)Absorbedsystemically:largedoseswillinduce
alkalosis.
(b)ProducesCO2instomach→distention,
discomfort,belching,riskofulcerperforation.
(c)Acidreboundoccurs,butisusuallyshort
lasting.
(d)IncreasesNa+load:mayworsenedemaand
CHF.
Useofsod.bicarbonateisrestrictedtocasual
treatmentofheartburn.Itprovidesquick
symptomaticrelief.
Otherusesaretoalkalinizeurineandtotreat
acidosis.
Theseareinsolubleandpoorly
absorbedbasiccompounds;
Reactinstomachtoformthe
correspondingchloridesalt.
Thechloridesaltagainreacts
withtheintestinalbicarbonateso
thatHCO3¯isnotsparedfor
absorption—no acid-base
disturbanceoccurs.
However,smallamountsthatare
absorbedhavethesame
alkalinizingeffectasNaHCO3.

13. Antacid combinations
(a)Fast(Mag.hydrox.)andslow(Alum.hydrox.)acting
componentsyieldpromptaswellassustainedeffect.
(b)Mag.saltsarelaxative,whilealum.saltsare
constipating:combinationmayannuleachother’saction
andbowelmovementmaybeleastaffected.
(c)Gastricemptyingisleastaffected;whilealum.salts
tendtodelayit,mag./cal.saltstendtohastenit.
(d)Doseofindividualcomponentsisreduced;systemic
toxicity(dependentonfractionalabsorption)is
minimized.

14. Drug interactions of Antacids
ByraisinggastricpHandbyformingcomplexes,the
non-absorbableantacidsdecreasetheabsorptionof
manydrugs,especiallytetracyclines,ironsalts,
fluoroquinolones,ketoconazole,H2blockers,
diazepam,phenothiazines,indomethacin,phenytoin,
isoniazid,ethambutolandnitrofurantoin.
Staggertheiradministrationby2hours.Theefficacyof
nitrofurantoinisalsoreducedbyalkalinizationof
urine.

15. ANTI-HELICOBACTER PYLORI DRUGS
The US-FDA approved regimen is: Lansoprazole 30 mg +
Amoxicillin 1000 mg+ clarithromycin500 mg, all given twice
daily for 2 weeks.
The National Formulary of India (NFI, 2010) suggests a
model H. pylori eradication regimen of 1 week consisting of:
Omeprazole40 mg OD + Metronidazole400 mg TDS
+ Amoxicillin 500 mg TDS.
Quadruple therapy with CBS 120 mg QID + tetracycline 500
mg QID + metronidazole400 mg TDS + omeprazole20 mg
BD is advocated for eradication failure cases.

16. Case Study
A45-year-oldmalepatientpresentswithdyspepsiaanddullepigastric
painwhichhasbeenworseninggraduallyoverthelastonemonth.The
painispartlyrelievedbyfood,butbecomesworseafter2hoursorso.
Heartburnandpainwhichawakenshimisoftenfeltatnight.Epigastric
tendernessisdetectedonpalpation.Uppergastrointestinalendoscopy
revealsanulcermeasuring12mmX18mminthe1stpartofduodenum.
Hismedicalrecordsshowthathesufferedsimilarepisodeofpainabout
9monthsago.Noendoscopywasdone,buthewastreatedwith
omeprazole20mgODfor6weeks.Subsequently,nearly3monthsback,
hesufferedfromloosemotionsandabdominalpainwhichwastreated
witha5daycourseofmetronidazole+norfloxacin.FacilityforH.pylori
testingisnotavailable.ThereisnohistoryofNSAIDuse.
Whatwouldbethemostappropriatetreatmentoptionforhimto
achievefastsymptomrelief,ulcerhealingandpreventionoffurther
recurrences?

17. Solution
Thispatientissufferingfromrecurrentpepticulcerdisease.Theearlier
episodeofsimilarsymptomshadrespondedtoprotonpumpinhibitor
(PPI)therapy.Therefore,itwasalsoduetopepticulcer.Symptomrelief
andulcerhealingcanbeachievedthistimeaswellwiththeuseofaPPI
givenfor4–8weeksdependingonendoscopicconfirmationofulcer
healing.However,italonecannotpreventrecurrences,whichmost
commonlyarecausedbypersistentcolonizationofupper
gastrointestinaltractbyH.pylori.Sincethesamecannotbeconfirmed
intheabsenceoftestingfacility,heshouldbegiventhebenefitofH.
pylorieradicationtherapywhichlargelypreventsulcerrecurrences.A3
drug,2weekregimenwouldbethemosteffectiveoption.Sincehehasa
historyofmetronidazoleuseintherecentpast,chancesof
nitroimidazoleresistancearehigh,andheshouldbetreatedwithaPPI
(omeprazole20mg/lansoprazole30mg/pantoprazole40
mg/rabeprazole20mg)+amoxicillin750mg+clarithromycin500mg,
allgiventwicedaily.ThePPIshouldthenbecontinuedtillendoscopic
confirmationofhealingisobtained,becausetheulcerwaslargerthan10
mmindiameter.